Post-cardiac Arrest Myocardial Dysfunction Research Articles

Cardiac arrest, stony heart, and cardiopulmonary resuscitation: An updated revisit.

The post-resuscitation period is recognized as the main predictor of cardiopulmonary resuscitation (CPR) outcomes. The first description of post-resuscitation syndrome and stony heart was published over 50 years ago. Major manifestations may include but are not limited to, persistent precipitating pathology, systemic ischemia/reperfusion response, post-cardiac arrest brain injury, and finally, post-cardiac arrest myocardial dysfunction (PAMD) after successful resuscitation. Why do some patients initially survive successful resuscitation, and others do not? Also, why does the myocardium response vary after resuscitation? These questions have kept scientists busy for several decades since the first successful resuscitation was described. By modifying the conventional modalities of resuscitation together with new promising agents, rescuers will be able to salvage the jeopardized post-resuscitation myocardium and prevent its progression to a dismal, stony heart. Community awareness and staff education are crucial for shortening the resuscitation time and improving short- and long-term outcomes. Awareness of these components before and early after the restoration of circulation will enhance the resuscitation outcomes. This review extensively addresses the underlying pathophysiology, management, and outcomes of post-resuscitation syndrome. The pattern, management, and outcome of PAMD and post-cardiac arrest shock are different based on many factors, including in-hospital cardiac arrest vs out-of-hospital cardiac arrest (OHCA), witnessed vs unwitnessed cardiac arrest, the underlying cause of arrest, the duration, and protocol used for CPR. Although restoring spontaneous circulation is a vital sign, it should not be the end of the game or lone primary outcome; it calls for better understanding and aggressive multi-disciplinary interventions and care. The development of stony heart post-CPR and OHCA remain the main challenges in emergency and critical care medicine.

Abstract 361: Effect of Percutaneous Ventricular Assisted Device on a Recovery of Myocardial Function in Swine Model With Prolonged Cardiac Arrest

Background: Percutaneous ventricular assist device (pLVAD) support and Transient aortic balloon occlusion (AO) can preserve cerebral and cardiac blood flow during cardiopulmonary resuscitation (CPR), but it remains unclear if pLVAD reduces post-cardiac arrest myocardial dysfunction. Hypothesis: pLVAD support immediately after the return of spontaneous circulation (ROSC) improves early recovery of myocardial function following prolonged cardiac arrest. Aims: Evaluate the association between early post-ROSC pLVAD support and recovery of myocardial function in a swine model of prolonged cardiac arrest. Methods: This is a secondary analysis of a subset of animals that achieved ROSC in a study comparing pLVAD, transient AO or both during CPR after prolonged cardiac arrest. pLVAD, aortic occlusion, or both were initiated after 24 minutes of ventricular fibrillation cardiac arrest (8 min no-flow and 16 min mechanical CPR). AO was discontinued post-ROSC, and pLVAD support or standard care were continued. Beginning 60 minutes post-ROSC, pLVAD support was weaned to <1.0 L/min while maintaining a MAP >70 mmHg, and subsequently removed at 4 hours when feasible. The primary outcome was the recovery of cardiac index (CI) and left ventricular ejection fraction (LVEF) at 4 hours post-ROSC. Data are shown as mean (standard error). Results: Seventeen animals achieved ROSC without complication and were included in this analysis (pLVAD group, n = 11 [8 were removed from pLVAD], and standard care group, n = 6). For the primary outcome, the pLVAD group had significantly higher CI of 4.2(0.3) vs. 3.1(0.4) L/min/m2 (p=0.043) and LVEF 60(3) vs. 49(4) % (p=0.029) at 4 hours after ROSC, respectively, when compared with the standard care group. Focusing on the early period within 60 minutes after ROSC when maximum pLVAD flow was maintained, the pLVAD group had significantly higher coronary perfusion pressure (62[4] vs. 47[5] mmHg, p=0.019), lower LV stroke work index (3.9[3.0] vs. 14.9[4.4] cJ/m2, p=0.043), and lower total pulmonary resistance index (13.2[4.8] vs. 21.5[14.4] Wood Unit, p=0.001). Conclusion: These results suggest that early pLVAD support after ROSC is associated with better recovery myocardial function compared to standard care after prolonged cardiac arrest.

Effect of percutaneous ventricular assisted device on post-cardiac arrest myocardial dysfunction in swine model with prolonged cardiac arrest

BackgroundIt remains unclear if percutaneous left ventricular assist device (pLVAD) reduces post-cardiac arrest myocardial dysfunction. MethodsThis is a prespecified analysis of a subset of swine that achieved return of spontaneous circulation (ROSC) in a study comparing pLVAD, transient aortic occlusion (AO), or both during cardiopulmonary resuscitation (CPR). Devices were initiated after 24 minutes of ventricular fibrillation cardiac arrest (8 min no-flow and 16 min mechanical CPR). AO was discontinued post-ROSC, and pLVAD support or standard care were continued. Beginning 60 minutes post-ROSC, pLVAD support was weaned to < 1.0 L/min and subsequently removed at 240 minutes. The primary outcome was cardiac index (CI), stroke volume index (SVI), and left ventricular ejection fraction (LVEF) at 240 minutes post-ROSC. Data are shown as mean (standard error). ResultsSeventeen swine achieved ROSC without complication and were included in this analysis (pLVAD group, n = 11 and standard care group, n = 6). For the primary outcomes, the pLVAD group had significantly higher CI of 4.2(0.3) vs. 3.1(0.4) L/min/m2 (p = 0.043) and LVEF 60(3) vs. 49(4) % (p = 0.029) at 240 minutes after ROSC when compared with the standard care group, while SVI was not statistically significantly different (32[3] vs. 23[4] mL/min/m2, p = 0.054). During the first 60 minutes post-ROSC, the pLVAD group had significantly higher coronary perfusion pressure, lower LV stroke work index, and total pulmonary resistance index. ConclusionThese results suggest that early pLVAD support after ROSC is associated with better recovery myocardial function compared to standard care after prolonged cardiac arrest.

Myocardial dysfunction after cardiac arrest: tips and pitfalls.

Postcardiac arrest shock (PCAS) is defined by hemodynamic instability occurring in the first hours after cardiac arrest (CA) and is a major cause of mortality among patients hospitalized after CA. It includes vasoplegia and myocardial dysfunction. This postcardiac arrest myocardial dysfunction is supposed to recover within the 3 days. However, there are many unknowns regarding its definition, its prognosis value and its management. In this review dedicated to emergency physicians, we choose to address tips and pitfalls they should know regarding this prevalent syndrome.

Prostaglandin E1 attenuates post‑cardiac arrest myocardial dysfunction through inhibition of mitochondria‑mediated cardiomyocyte apoptosis.

Post-cardiac arrest myocardial dysfunction (PAMD) is a leading cause of death in patients undergoing resuscitation patients following cardiac arrest (CA). Although prostaglandin E1 (PGE1) is a clinical drug used to mitigate ischemia injury, its effect on PAMD remains unknown. In the present study, the protective effects of PGE1 on PAMD were evaluated in a rat model of CA and in a hypoxia-reoxygenation (H/R) in vitro model. Rats were randomly assigned to CA, CA+PGE1 or sham groups. Asphyxia for 8 min followed by cardiopulmonary resuscitation were performed in the CA and CA+PGE1 groups. PGE1 was intravenously administered at the onset of return of spontaneous circulation (ROSC). PGE1 treatment significantly increased the ejection fraction and cardiac output within 4 h following ROSC and improved the survival rate, compared with the CA group. Moreover, PGE1 inactivated GSK3β, prevented mitochondrial permeability transition pore (mPTP) opening, while reducing cytochrome c and cleaved caspase-3 expression, as well as cardiomyocyte apoptosis in the rat model. To examine the underlying mechanism, H/R H9c2 cells were treated with PGE1 at the start of reoxygenation. The changes in GSK3β activity, mPTP opening, cytochrome c and cleaved caspase-3 expression, and apoptosis of H9c2 cells were consistent with those noted in vivo. The results indicated that PGE1 attenuated PAMD by inhibiting mitochondria-mediated cardiomyocyte apoptosis.

Cardiac function after cardiac arrest: what do we know?

Postcardiac arrest myocardial dysfunction (PCAMD) is a frequent complication faced during post-resuscitation care that adversely impacts survival and neurological outcome. Both mechanical and electrical factors contribute to the occurrence of PCAMD. Prearrest ventricular function, the cause of cardiac arrest, global ischemia, resuscitation factors, ischemia/reperfusion injury and post-resuscitation treatments contribute to the severity of PCMAD. The pathophysiology of PCAMD is complex and include myocytes energy failure, impaired contractility, cardiac edema, mitochondrial damage, activation of inflammatory pathways and the coagulation cascade, persistent ischemic injury and myocardial stiffness. Hypotension and low cardiac output with vasopressor/inotropes need are frequent after resuscitation. However, clinical, hemodynamic and laboratory signs of shock are frequently altered by cardiac arrest pathophysiology and post-resuscitation treatment, potentially being misleading and not fully reflecting the severity of postcardiac arrest syndrome. Even if validated criteria are lacking, an extensive hemodynamic evaluation is useful to define a "benign" and a "malign" form of myocardial dysfunction and circulatory shock, potentially having treatment and prognostic implications. Cardiac output is frequently decreased after cardiac arrest, particularly in patients treated with target temperature management (TTM); however, it is not independently associated with outcome. Sinus bradycardia during TTM seems independently associated with survival and good neurological outcome, representing a promising prognostic indicator. Higher mean arterial pressure (MAP) seems to be associated with improved survival and cerebral function after cardiac arrest; however, two recent randomized clinical trials failed to replicate these results. Recommendations on hemodynamic optimization are relatively poor and are largely based on general principle of intensive care medicine.

Aldehyde Dehydrogenase 2 Protects Against Post-Cardiac Arrest Myocardial Dysfunction Through a Novel Mechanism of Suppressing Mitochondrial Reactive Oxygen Species Production.

Post-cardiac arrest myocardial dysfunction significantly contributes to early mortality after the return of spontaneous circulation. However, no effective therapy is available now. Aldehyde dehydrogenase 2 (ALDH2) enzyme has been shown to protect the heart from aldehyde toxicity such as 4-hydroxy-2-nonenal (4-HNE) and oxidative stress. In this study, we evaluated the effect of enhanced activity or expression of ALDH2 on post-cardiac arrest myocardial dysfunction and survival in a rat cardiac arrest model. Furthermore, we elucidated the underlying mechanisms with a focus on mitochondrial reactive oxygen species (ROS) production in a cell hypoxia/reoxygenation model. A total of 126 rats were used for the ALDH2 activation or cardiac overexpression of ALDH2 studies. Randomization was done 10 min before the respective agonist injection or in vivo gene delivery. We showed that enhanced activity or expression of ALDH2 significantly improved contractile function of the left ventricle and survival rate in rats subjected to cardiac arrest-cardiopulmonary resuscitation procedure. Moreover, ALDH2 prevented cardiac arrest-induced cardiomyocyte death from apoptosis and mitochondrial damage. Mechanistically, 4-HNE, a representative substrate of ALDH2, was dominantly increased in the hypoxia/reoxygenation-exposed cardiomyocytes. Direct addition of 4-HNE led to significantly augmented succinate accumulation and mitochondrial ROS production. Through metabolizing 4-HNE, ALDH2 significantly inhibited mitochondrial ROS production. Our findings provide compelling evidence of the cardioprotective effects of ALDH2 and therapeutic targeting this enzyme would provide an important approach for treating post-cardiac arrest myocardial dysfunction.

Protective effect of carbon monoxide releasing molecules 2 on post-resuscitation myocardial dysfunction in rats

Objective: To investigate the protective effect of carbon monoxide releasing molecule 2 (CORM-2) on post-resuscitation myocardial dysfunction in rats. Methods: Forty male SD rats which were healthy were randomly divided into 5 groups: sham operated group(sham group), cardiopulmonary resuscitation(PCR) group, DMSO group, inactivated CORM-2(iCORM-2) group and CORM-2 group (n=8 each). Established the model of post-cardiac arrest myocardial dysfunction by intravenous potassium chloride (4 ℃) injection combined with asphyxiation for 4 minutes and then followed by artificial chest compression for 3 minutes. Sham group: rats were instrumented with catheter without inducing cardiac arrest and resuscitation, and intraperitoneal injection of 0.9% normal saline (4 ml/kg) was performed 12 hours before catheterization. CPR group: rats were instrumented with catheters and underwent CPR, and intraperitoneal injection of 0.9% normal saline (4 ml/kg) was performed 12 hours before surgery.CORM-2 group: rats were instrumented with catheters and underwent CPR, intraperitoneally injected the prepared CORM-2 solution (4 mg/kg) at 12 hours before surgery. DMSO group: rats were instrumented with catheters and underwent CPR, intraperitoneally injected the prepared DMSO solution (4 ml/kg) at 12 hours before surgery. iCORM-2 group: rats were instrumented with catheters and underwent CPR, iCORM-2 solution (4 mg/kg) was intraperitoneally injected at 12 hours before surgery. Hemodynamic data (MAP, +dp/dtmax, -dp/dt) were continuously monitored and recorded for 4 hours after resuscitation (or catheterization) in each group. Myocardial tissue specimen and blood samples were taken after resuscitation (or catheterization). The myocardial ultrastructure was observed by transmission electron microscope. Lactate dehydrogenase (LDH) activity was measured by lactate-pyruvate method. Serum creatine kinase isoenzyme (CK-MB) concentration was measured by ELISA. Western blot was used to detect the levels of Caspase-3, Caspase-9 and Cyt-C protein in myocardial tissue. Results: MAP, +dp/dtmax and -dp/dt at 0.5, 1, 2, 3 and 4 hours post resuscitation were significantly lower than those immediately after catheterization in CRP, DMSO, iCORM-2 groups (all P<0.05). MAP at 0.5, 1, 2, 3, and 4 hours post resuscitation were significantly lower in CRP, DMSO and iCORM-2 groups than those at respective time points in sham group (all P<0.05), while MAP was similar between CORM-2 group and Sham group at these time points (all P>0.05). +dp/dtmax and -dp/dt values at 0.5, 1, 2, 3, and 4 hours post resuscitation were lower than those at respective time points in sham group and significance was found at 0.5, 1 and 2 hours post resuscitation (both P<0.05), while +dp/dtmax and -dp/dt values were similar between CORM-2 group and sham group at various time points (all P>0.05). Myocardial ultrastructure, especially mitochondrial structural integrity was better preserved in the CORM-2 group than those in the other resuscitation groups at 4 hours after resuscitation. Serum LDH activity and CK-MB concentration were significantly elevated at 4 hours after resuscitation in the CPR group, DMSO group and iCORM-2 group than those in sham group (all P<0.01); CK-MB concentration was also higher in CORM-2 group than that in sham group,and LDH level was similar between CORM-2 group and sham group (P>0.05). Serum LDH activity and CK-MB concentrations were significantly lower in the CORM-2 group than those in the other resuscitation groups (all P<0.01). The myocardial expressions of Caspase-3, Caspase-9 and Cyt-C at 4 hours after resuscitation were significantly higher in the CPR group, DMSO group and iCORM-2 group than those in sham group; the myocardial expressions of Caspase-3 and Caspase-9 were significantly higher in CORM-2 group than those in sham group (both P<0.05), while Cyt-C expression was similar between CORM-2 group and sham group. The expressions of the above 3 proteins were significantly lower in the CORM-2 group than those in the other resuscitation groups (all P<0.05). Conclusions: CORM-2 can effectively alleviate post-resuscitation myocardial injury in rats with cardiopulmonary resuscitation and improve cardiac function. Protecting myocardial mitochondria and inhibiting mitochondrial apoptosis pathway may serve as the protective mechanisms in this model.

Effect of prolonged targeted temperature management on left ventricular myocardial function after out-of-hospital cardiac arrest − A randomised, controlled trial

AimTo evaluate post-cardiac arrest myocardial dysfunction during prolonged targeted temperature management (TTM) compared with standard TTM in comatose out-of-hospital cardiac arrest (OHCA) survivors. MethodsA randomised, controlled trial comparing myocardial function after TTM at 33 ±1°C for 48h compared with 24h. A total of 105 OHCA patients were computer-randomised to 24h (n=50) or 48h (n=55) of TTM. Transthoracic echocardiography was performed after 24h, 48h and 72h. Echocardiographic parameters were evaluated by an investigator who was blinded to randomisation. The primary endpoint was peak systolic mitral annular velocity (Ś) measured as the difference in the period from 24h to 72h. The model was adjusted for age, primary rhythm and heart rate. The secondary outcomes were global peak longitudinal strain, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE) and the diastolic measures e’ and E/e’. ResultsThe mean difference of S’ was significantly increased in the 48h group compared with the 24h group: −1.14cm/s (−1.83; −0.45), p=0.001. This difference was consistent after adjusting the data (p=0.008). However, there were no significant changes between the study groups with respect to the adjusted secondary outcomes of global peak longitudinal strain (p=0.07), LVEF (p=0.31), TAPSE (p=0.91), e’ (p=0.26) and E/e’ (p=0.18). ConclusionProlonged TTM at 33°C of 48h compared with 24h in comatose OHCA survivors may improve the recovery of post-cardiac arrest left myocardial dysfunction demonstrated by the echocardiographic outcome, S’.ClinicalTrials.gov identifier: NCT02066753.

Abstract 12857: Echocardiographic Patterns of Post-cardiac Arrest Myocardial Dysfunction

Purpose: Post-cardiac arrest myocardial dysfunction can be developed after successful resuscitation from cardiac arrest. However, echocardiographic patterns of post-cardiac arrest myocardial dysfunction are not yet known. The purpose of this study was to investigate the manifestations of post-cardiac arrest myocardial dysfunction with serial echocardiography during post-cardiac arrest period. Materials and Methods: We enrolled non-traumatic out-of-hospital cardiac arrest patients older than 18 years old who were successfully resuscitated after CPR. The patients with myocardial infarction and pre-existing cardiac disease including heart failure or myocardial disease were excluded. Transthoracic echocardiography was performed within 24 hours, between 24 to 48 hours, after 48 hour since restoration of spontaneous circulation (ROSC) was achieved. Results: Out of 263 patients, 186 patients (122 males) were enrolled in the analysis. No left ventricular (LV) dysfunction was observed in 120 patients (64.5%). Abnormal LV dysfunction was observed in 66 patients (35.5%). Abnormal LV dysfunctions included global hypokinesis in 32 patients (17.2%), regional wall motion abnormalities (RWMA) in 25 patients (13.4%), and abnormalities like stress-induced cardiomyopathy in 9 patients (4.8%). There were no differences in etiology (p=0.275), duration of cardiac arrest (p=0.078), cumulative dose of epinephrine (p=0.336), and hospital mortality (p=0.140) according to the pattern of post-cardiac arrest myocardial dysfunction. In subgroup analysis of the patients with shockable rhythm, cumulative defibrillation energy (joules) was lower in patients without LV dysfunction (101±41) than in patients with RWMA (200±74) or global hypokinesis (408±131) (p=0.011). Cut-off value of 220 J had 21% of sensitivity and 91% of specificity for development of LV dysfunction (AUC=0.572). Conclusion: Post-cardiac arrest myocardial dysfunction occurs in one thirds of patients resuscitated from cardiac arrest. Echocardiographic patterns of post-cardiac arrest LV dysfunction include global hypokinesis, regional wall motion abnormalities, and abnormalities like stress-induced cardiomyopathy.

Urocortin Treatment Improves Acute Hemodynamic Instability and Reduces Myocardial Damage in Post-Cardiac Arrest Myocardial Dysfunction.

AimsHemodynamic instability occurs following cardiac arrest and is associated with high mortality during the post-cardiac period. Urocortin is a novel peptide and a member of the corticotrophin-releasing factor family. Urocortin has the potential to improve acute cardiac dysfunction, as well as to reduce the myocardial damage sustained after ischemia reperfusion injury. The effects of urocortin in post-cardiac arrest myocardial dysfunction remain unclear.Methods and ResultsWe developed a preclinical cardiac arrest model and investigated the effects of urocortin. After cardiac arrest induced by 6.5 min asphyxia, male Wistar rats were resuscitated and randomized to either the urocortin treatment group or the control group. Urocortin (10 μg/kg) was administrated intravenously upon onset of resuscitation in the experimental group. The rate of return of spontaneous circulation (ROSC) was similar between the urocortin group (76%) and the control group (72%) after resuscitation. The left ventricular systolic (dP/dt40) and diastolic (maximal negative dP/dt) functions, and cardiac output, were ameliorated within 4 h after ROSC in the urocortin-treated group compared to the control group (P<0.01). The neurological function of surviving animals was better at 6 h after ROSC in the urocortin-treated group (p = 0.023). The 72-h survival rate was greater in the urocortin-treated group compared to the control group (p = 0.044 by log-rank test). Cardiomyocyte apoptosis was lower in the urocortin-treated group (39.9±8.6 vs. 17.5±4.6% of TUNEL positive nuclei, P<0.05) with significantly increased Akt, ERK and STAT-3 activation and phosphorylation in the myocardium (P<0.05).ConclusionsUrocortin treatment can improve acute hemodynamic instability as well as reducing myocardial damage in post-cardiac arrest myocardial dysfunction.

Echocardiographic patterns of post-cardiac arrest myocardial dysfunction

Echocardiographic patterns of post-cardiac arrest myocardial dysfunction

In Vivo Post-Cardiac Arrest Myocardial Dysfunction Is Supported by Ca2+/Calmodulin-Dependent Protein Kinase II-Mediated Calcium Long-Term Potentiation and Mitigated by Alda-1, an Agonist of Aldehyde Dehydrogenase Type 2.

Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo. We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo. Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.

Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction.

While therapeutic hypothermia improves the outcomes of individuals in cardiac arrest, the hemodynamic responses and mechanisms which underlie hypothermia-induced cardioprotection are not fully understood. Therefore, we investigated the mechanism by which induced hypothermia preserves cardiac function and protects against mitochondrial damage following cardiac arrest. Cardiac arrest was induced in adult male Wistar rats by asphyxiation for 8.5min. Following resuscitation, the animals were randomly assigned to a hypothermia (32°C) or normothermia (37°C) group. Monitoring results showed that cardiac output at the fourth hour after resuscitation was significantly better in rats treated with hypothermia when compared to rats treated with normothermia (P<0.01). Examinations by transmission electron microscopy showed that mitochondria in the left ventricle of rats in the hypothermia group were significantly less swollen compared to such mitochondria in the normothermia group (P<0.001). Additionally, opening of mitochondrial permeability transition pores occurred less frequently in the hypothermic group. While complex I/III activity in the electron transport reaction was damaged after cardiac arrest and resuscitation, the degree of injury was ameliorated by hypothermia treatment (P<0.05). The amount of STAT-3 phosphorylated at tyrosine 705 and its expression in mitochondria were significantly higher under hypothermia treatment compared to normothermia treatment. In vitro studies showed that inhibition STAT-3 activation abolished the ability of hypothermia to protect H9C2 cardiomyocytes against injury produced by simulated ischemia and reperfusion. Therapeutic hypothermia treatment can ameliorate cardiac dysfunction and help preserve both mitochondrial integrity and electron transport activity.

Cardiocerebral protection by emulsified isoflurane during cardiopulmonary resuscitation

Although improvement in cardiopulmonary resuscitation (CPR) performance and the increasing success at achieving return of spontaneous circulation (ROSC) have been possible in recent years, the survival and discharge rates of post-cardiac arrest (CA) patients remain disappointing. The high mortality rate is attributed to whole-body ischemia/reperfusion (I/R) induced multi-organ dysfunction that is well known as post-cardiac arrest syndrome. Post-cardiac arrest myocardial dysfunction and brain injury are the main clinical features of this complex pathophysiological process. Previous evidences have shown that volatile anesthetics, such as isoflurane, trigger a powerful and highly integrated cell survival response during I/R period in multiple organs, including heart and brain, which reduces I/R injury. This effect that called anesthetic-induced postconditioning can be shown when volatile anesthetics are administered after the onset of ischemia and at the time of reperfusion. Emulsified isoflurane (EIso) is a new anesthetic for intravenous administration, which is conveniently feasible outside operating room. Therefore, we hypothesize that EIso postconditioning could provide the cardiocerebral protection, and combined with therapeutic hypothermia as sedative agent could produce enhanced cardiocerebral protection, which can result in significant improvement of neurologically intact post-cardiac arrest survival. We consider that it would become a feasible, safe and efficient cardiocerebral protective intervention in the prevention and alleviation of post-cardiac arrest syndrome, which would also improve the outcomes after CA.

Abstract 317: Pre-Hospital Predictors of Post-Cardiac Arrest Left Ventricle Dysfunction

Background: A proportion of patients with out-of-hospital cardiac arrest are initially resuscitated; however, few survive to hospital discharge. A common cause of this high mortality rate is post-cardiac arrest myocardial dysfunction, a temporal phenomenon that can be fully recovered from with appropriate treatment. Objectives: This study aims to explore the predictors of post-cardiac arrest myocardial dysfunction and evaluate their influence on survival and neurologic outcome. We hypothesized that there would be an association between pre-hospital resuscitative strategies (such as witnessed arrest, bystander CPR, and the use of a publicly accessible AED) and development of LV dysfunction after resuscitation. Methods: A retrospective chart review was performed of 238 out-of-hospital cardiac arrest patients who underwent echocardiography after resuscitation at three hospitals. Pre-hospital arrest characteristics and echocardiography results were abstracted. The primary outcome was left ventricular ejection fraction (LVEF; abnormal defined as &lt;40%) in the first 24 hours. Results: 191 (80%) patients had an echo completed in the first 24 hours, of which abnormal LVEF was observed in 90 (47%).Having a witnessed arrest predicted abnormal LVEF in first 24 hours (OR, 3.7; 95% CI, 1.04-13.22). No association was detected between initial rhythm, bystander CPR, use of AED, total downtime and the development of LVEF. No difference was observed in both neurologic outcome and survival in patients with a normal versus abnormal 24 hour echo. Among the 51 patients with serial echos, 28 (55%) patients had an abnormal initial LVEF; 15 (54%) of these patients had an LVEF that returned to normal by 72 hours. Conclusions: In survivors of out-of-hospital cardiac arrest, abnormal LVEF after resuscitation is not predictive of outcome; however, witnessed arrest is associated with the development of abnormal LVEF.

Therapeutic Hypothermia Activates the Endothelin and Nitric Oxide Systems after Cardiac Arrest in a Pig Model of Cardiopulmonary Resuscitation

Post-cardiac arrest myocardial dysfunction is a major cause of mortality in patients receiving successful cardiopulmonary resuscitation (CPR). Mild therapeutic hypothermia (MTH) is the recommended treatment after resuscitation from cardiac arrest (CA) and is known to exert neuroprotective effects and improve short-term survival. Yet its cytoprotective mechanisms are not fully understood. In this study, our aim was to determine the possible effect of MTH on vasoactive mediators belonging to the endothelin/nitric oxide axis in our porcine model of CA and CPR. Pigs underwent either untreated CA or CA with subsequent CPR. After state-of-the-art resuscitation, the animals were either left untreated, cooled between 32–34°C after ROSC or treated with a bolus injection of S-PBN (sodium 4-[(tert-butylimino) methyl]benzene-3-sulfonate N-oxide) until 180 min after ROSC, respectively. The expression of endothelin 1 (ET-1), endothelin converting enzyme 1 (ECE-1), and endothelin A and B receptors (ETAR and ETBR) transcripts were measured using quantitative real-time PCR while protein levels for the ETAR, ETBR and nitric oxide synthases (NOS) were assessed using immunohistochemistry and Western Blot. Our results indicated that the endothelin system was not upregulated at 30, 60 and 180 min after ROSC in untreated postcardiac arrest syndrome. Post-resuscitative 3 hour-long treatments either with MTH or S-PBN stimulated ET-1, ECE-1, ETAR and ETBR as well as neuronal NOS and endothelial NOS in left ventricular cardiomyocytes. Our data suggests that the endothelin and nitric oxide pathways are activated by MTH in the heart.

Post-cardiac Arrest Syndrome in Children.

Although sustained return of spontaneous circulation (ROSC) can be initially established after resuscitation in children, many of the children do not survive to discharge because they developped a post cardiac arrest syndrome. The post-cardiac arrest syndrome includes systemic ischaemia/reperfusion response, post-cardiac arrest brain injury, postcardiac arrest myocardial dysfunction, and persistent precipitating pathology. The main cause of death after ROSC in children is brain injury. Physiopathology and management are reviewed in regards of pediatric specificities. Management according to ABCDE includes airway and ventilation management, oxygen therapy, hemodynamic management with early goal directed therapy and protection of the brain against secondary injury by therapeutic hypothermia, management of seizures and control of glycemia.

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Introduction: Post-cardiac arrest myocardial dysfunction (MD) is a well recognized and common phenomenon. Understanding this phenomenon and its effect on neurologic outcome is important to the successful management of post-cardiac arrest patients. There are no clinical studies evaluating the effect of MD on outcome in post-cardiac arrest patients treated with Therapeutic Hypothermia (TH). Hypothesis: The objective of this study was to determine whether MD in post-cardiac arrest patients treated with TH is associated with worse neurologic outcome. MD is defined as global dysfunction on echocardiogram with ejection fraction (EF) < 30% within 48 hours of cardiac arrest. Methods: Review of consecutive post-cardiac arrest comatose adult patients treated with TH between May 2009 and December 2010. Demographic data, time to return of spontaneous circulation (ROSC), time to target temperature (TTT), echocardiogram findings, survival, and neurologic outcomes using cerebral performance category (CPC) scale at hospital discharge were prospectively recorded. Results: A total of 71 patients were enrolled. All patients received TH, with a target temperature of 33 oC for 24 hours. Patients with MD (n = 13) were matched with control group (EF > 30%, n = 58) on baseline characteristics, age (63 +/- 17 vs 62 +/- 15, in years), time to ROSC (18.2 vs 19.2, in minutes), and TTT (566+/-331 vs 502+/-268, in minutes) respectively. A CPC score of 1–2 represents a good outcome and a CPC score of 3–5, a bad outcome. 84.6 % (11/13) of MD patients had poor outcome versus 51.7 % (30/58) of control patients had poor outcome (p = 0.05). Myocardial dysfunction had an odds ratio for poor outcome of 5.1 (95% confidence interval, 1.1-25.1, p=0.05). Conclusions: Among a small number of post-cardiac arrest comatose adult patients treated with therapeutic hypothermia, patients who developed myocardial dysfunction (EF<30%) had worse outcomes compared with patients who had EF > 30%. This provides scientific rationale for large prospective clinical trials evaluating the effect of myocardial dysfunction on outcome in post-cardiac arrest comatose patients treated with therapeutic hypothermia.

Post-cardiac arrest myocardial dysfunction is improved with cyclosporine treatment at onset of resuscitation but not in the reperfusion phase

Aim of study Significant myocardial dysfunction and high mortality occur after whole-body ischaemia-eperfusion injuries in the post-cardiac arrest status. The inhibition of mitochondrial permeability transition pore (mPTP) opening during ischaemia-reperfusion can ameliorate injuries in the specific organs. We investigated the effect and therapeutic window of pharmacological inhibition of mPTP opening in cardiac arrest. Methods Forty male Wistar rats were resuscitated after cardiac arrest induced by 8.5 min of asphyxia. Cyclosporine (10 mg/kg) was administered intravenously at onset of resuscitation in protocol 1 study and administered 3 min after ROSC in protocol 2 with placebo control in both. Results Left ventricular systolic (dP/dt40), diastolic (maximal negative dP/dt) functions and cardiac output were improved in the group with cyclosporine treatment at onset of resuscitation compared to control group (p < 0.01, respectively). Seventy-two hour survival was better in the group with cyclosporine treatment at onset of resuscitation compared to control (p = 0.046). Left ventricular systolic and diastolic function, cardiac output and 72 h survival were not improved in the group with cyclosporine treatment 3 min after ROSC. The severity of mitochondrial damage under electronic microscopy, mPTP opening, mitochondrial respiratory control ratio and ADP:O ratio were ameliorated in the group with cyclosporine treatment at onset of resuscitation (p< 0.05, respectively) but not in the group with cyclosporine treatment at 3 min after ROSC. Conclusions Post-cardiac arrest myocardial dysfunction and survival can be improved by cyclosporine treatment at onset of resuscitation, but not by the cyclosporine treatment at 3 min after ROSC.