Association between the triglyceride-glucose index and in-hospital major adverse cardiovascular events in patients with acute coronary syndrome: results from the Improving Care for Cardiovascular Disease in China (CCC)-Acute Coronary Syndrome project.

OBJECTIVE: Although the TyG index is a reliable predictor of insulin resistance (IR) and cardiovascular disease, its effectiveness in predicting major adverse cardiac events in hospitalized acute coronary syndrome (ACS) patients has not been validated in large-scale studies. In this study, we aimed to explore the association between the TyG index and the occurrence of MACEs during hospitalization. METHODS: We recruited ACS patients from the CCC-ACS (Improving Cardiovascular Care in China-ACS) database and calculated the TyG index using the formula ln(fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). These patients were classified into four groups based on quartiles of the TyG index. The primary endpoint was the occurrence of MACEs during hospitalization, encompassing all-cause mortality, cardiac arrest, myocardial infarction (MI), and stroke. We performed Cox proportional hazards regression analysis to clarify the correlation between the TyG index and the risk of in-hospital MACEs among patients diagnosed with ACS. Additionally, we explored this relationship across various subgroups. RESULTS: A total of 101,113 patients were ultimately included, and 2759 in-hospital MACEs were recorded, with 1554 (49.1%) cases of all-cause mortality, 601 (21.8%) cases of cardiac arrest, 251 (9.1%) cases of MI, and 353 (12.8%) cases of stroke. After adjusting for confounders, patients in TyG index quartile groups 3 and 4 showed increased risks of in-hospital MACEs compared to those in quartile group 1 [HR = 1.253, 95% CI 1.121-1.400 and HR = 1.604, 95% CI 1.437-1.791, respectively; p value for trend < 0.001], especially in patients with STEMI or renal insufficiency. Moreover, we found interactions between the TyG index and age, sex, diabetes status, renal insufficiency status, and previous PCI (all p values for interactions < 0.05). CONCLUSIONS: In patients with ACS, the TyG index was an independent predictor of in-hospital MACEs. Special vigilance should be exercised in females, elderly individuals, and patients with renal insufficiency.

Phospholipid Screening Postcardiac Arrest Detects Decreased Plasma Lysophosphatidylcholine: Supplementation as a New Therapeutic Approach.

OBJECTIVES: Cardiac arrest and subsequent resuscitation have been shown to deplete plasma phospholipids. This depletion of phospholipids in circulating plasma may contribute to organ damage postresuscitation. Our aim was to identify the diminishment of essential phospholipids in postresuscitation plasma and develop a novel therapeutic approach of supplementing these depleted phospholipids that are required to prevent organ dysfunction postcardiac arrest, which may lead to improved survival. DESIGN: Clinical case control study followed by translational laboratory study. SETTING: Research institution. PATIENTS/SUBJECTS: Adult cardiac arrest patients and male Sprague-Dawley rats. INTERVENTIONS: Resuscitated rats after 10-minute asphyxial cardiac arrest were randomized to be treated with lysophosphatidylcholine specie or vehicle. MEASUREMENTS AND MAIN RESULTS: We first performed a phospholipid survey on human cardiac arrest and control plasma. Using mass spectrometry analysis followed by multivariable regression analyses, we found that plasma lysophosphatidylcholine levels were an independent discriminator of cardiac arrest. We also found that decreased plasma lysophosphatidylcholine was associated with poor patient outcomes. A similar association was observed in our rat model, with significantly greater depletion of plasma lysophosphatidylcholine with increased cardiac arrest time, suggesting an association of lysophosphatidylcholine levels with injury severity. Using a 10-minute cardiac arrest rat model, we tested supplementation of depleted lysophosphatidylcholine species, lysophosphatidylcholine(18:1), and lysophosphatidylcholine(22:6), which resulted in significantly increased survival compared with control. Furthermore, the survived rats treated with these lysophosphatidylcholine species exhibited significantly improved brain function. However, supplementing lysophosphatidylcholine(18:0), which did not decrease in the plasma after 10-minute cardiac arrest, had no beneficial effect. CONCLUSIONS: Our data suggest that decreased plasma lysophosphatidylcholine is a major contributor to mortality and brain damage postcardiac arrest, and its supplementation may be a novel therapeutic approach.

Serum proteomic analysis of novel predictive serum proteins for neurological prognosis following cardiac arrest.

Early prognostication of neurological outcome in comatose patients after cardiac arrest (CA) is vital for clinicians when assessing the survival time of sufferers and formulating appropriate treatment strategies to avoid the withdrawal of life-sustaining treatment (WLST) from patients. However, there is still a lack of sensitive and specific serum biomarkers for early and accurate identification of these patients. Using an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomic approach, we discovered 55 differentially expressed proteins, with 39 up-regulated secreted serum proteins and 16 down-regulated secreted serum proteins between three comatose CA survivors with good versus poor neurological recovery. Then, four proteins were selected and were validated via an enzyme-linked immunosorbent assay (ELISA) approach in a larger-scale sample containing 32 good neurological outcome patients and 46 poor neurological outcome patients, and it was confirmed that serum angiotensinogen (AGT) and alpha-1-antitrypsin (SERPINA1) were associated with neurological function and prognosis in CA survivors. A prognostic risk score was developed and calculated using a linear and logistic regression model based on a combination of AGT, SERPINA1 and neuron-specific enolase (NSE) with an area under the curve of 0.865 (P < .001), and the prognostic risk score was positively correlated with the CPC value (R = 0.708, P < .001). We propose that the results of the risk score assessment not only reveal changes in biomarkers during neurological recovery but also assist in enhancing current therapeutic strategies for comatose CA survivors.

Autoantibody Signature in Cardiac Arrest.

BACKGROUND: Cardiac arrest is a tragic event that causes 1 death roughly every 90 seconds worldwide. Survivors generally undergo a workup to identify the cause of arrest. However, 5% to 10% of cardiac arrests remain unexplained. Because cardiac arrhythmias underlie most cardiac arrests and increasing evidence strongly supports the involvement of autoantibodies in arrhythmogenesis, a large-panel autoantibody screening was performed in patients with cardiac arrest. METHODS: This is an observational, cross-sectional study of patients from the Montreal Heart Institute hospital cohort, a single-center registry of participants. A peptide microarray was designed to screen for immunoglobulin G targeting epitopes from all known cardiac ion channels with extracellular domains. Plasma samples from 23 patients with unexplained cardiac arrest were compared with those from 22 patients with cardiac arrest cases of ischemic origin and a group of 29 age-, sex-, and body mass index-matched healthy subjects. The false discovery rate, least absolute shrinkage and selection operator logistic regression, and random forest methods were carried out jointly to find significant differential immunoglobulin G responses. RESULTS: The autoantibody against the pore domain of the L-type voltage-gated calcium channel was consistently identified as a biomarker of idiopathic cardiac arrest (P=0.002; false discovery rate, 0.007; classification accuracies ≥0.83). Functional studies on human induced pluripotent stem cell-derived cardiomyocytes demonstrated that the anti-L-type voltage-gated calcium channel immunoglobulin G purified from patients with idiopathic cardiac arrest is proarrhythmogenic by reducing the action potential duration through calcium channel inhibition. CONCLUSIONS: The present report addresses the concept of autoimmunity and cardiac arrest. Hitherto unknown autoantibodies targeting extracellular sequences of cardiac ion channels were detected. Moreover, the study identified an autoantibody signature specific to patients with cardiac arrest.

Serum neurofilament measurement improves clinical risk scores for outcome prediction after cardiac arrest: results of a prospective study.

BACKGROUND: A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. METHODS: This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. RESULTS: Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p < 0.001) and CAHP score (from AUC 0.89 to 0.92, p < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 (p < 0.001) for OHCA and 0.83 (p < 0.001) for CAHP. CONCLUSIONS: Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

The optimal peripheral oxygen saturation may be 95-97% for post-cardiac arrest patients: A retrospective observational study.

BACKGROUND: Current post-resuscitation guidelines recommend oxygen titration in adults with the return of spontaneous circulation after cardiac arrest. However, the optimal peripheral oxygen saturation (SpO2) is still unclear for post-cardiac arrest care. METHODS: We conducted a retrospective observational study of prospectively collected data of all cardiac arrest patients admitted to the intensive care units between 2014 and 2015. The main exposure was SpO2, which were interfaced from bedside vital signs monitors as 1-min averages, and archived as 5-min median values. The proportion of time spent in different SpO2 categories was included in separate multivariable regression models along with covariates. The primary outcome measure was hospital mortality and the proportion of discharged home as the secondary outcome was reported. RESULTS: 2836 post-cardiac arrest patients in ICUs of 156 hospitals were included. 1235 (44%) patients died during hospitalization and 818 (29%) patients discharged home. With multivariate regression analysis, the proportion of time spent in SpO2 of ≤89%, 90%, 91%, and 92% were associated with higher hospital mortality. The proportion of time spent in SpO2 of 95%, 96%, and 97% were associated with a higher proportion of discharged home outcome, but not associated with hospital mortality. CONCLUSIONS: In this retrospective observational study, the optimal SpO2 for patients admitted to the intensive care unit after cardiac arrest may be 95-97%. Further investigation is warranted to determine if targeting SpO2 of 95-97% would improve patient-centered outcomes after cardiac arrest.

High plasma levels of pro-inflammatory factors interleukin-17 and interleukin-23 are associated with poor outcome of cardiac-arrest patients: a single center experience.

BACKGROUND: Systemic inflammation is an important feature of post-cardiac arrest syndrome (PCAS). This study was designed to determine whether the plasma concentrations of some circulating pro-inflammatory cytokines (interleukin-17 [IL-8], IL-22, IL-23 and IL-33) are of value in predicting the outcome of patients after return of spontaneous circulation (ROSC) during the post-cardiac arrest period. METHODS: This was a prospective observational clinical study. In total, 21 patients (survivors, n = 10; non-survivors, n = 11) who experienced cardiac arrest and successful ROSC with expected survival of at least 7 days were consecutively enrolled from January 2016 to December 2017. Of the 21 enrolled patients, ten survived were designated "survivors". The other eleven patients died between 2 days and 1 months post ROSC. Venous blood was drawn at three time-points: baseline (< 1 h post ROSC), 2 days post ROSC and 7 days post ROSC. Plasma IL-8, IL-22, IL-23 and IL-33 were determined using commercial enzyme-linked immunosorbent assays. RESULTS: Plasma creatinine levels, but aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were elevated in non-survivors compared with survivors. Plasma levels of IL-17, IL-22, IL-23 and IL-33 of the 21 total patients did not change at 2 or 7 days post ROSC compared to baseline. In survivors, the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were lower than baseline. In non-survivors, plasma levels of IL-17 increased compared with baseline. Receiver operating characteristic curve analysis showed that the plasma levels of IL-17 and IL-23 at 2 or 7 days post ROSC were able to predict the mortality of PCAS patients, and positively correlated with Acute Physiology and Chronic Health Evaluation (APACHE)-II score and time to ROSC. CONCLUSION: These results provide the first evidence that the elevated plasma IL-17 and IL-23 levels are associated with poor outcome in PCAS patients. The role of IL-17/IL-23 axis post ROSC is worth paying attention to in PCAS patients. TRIAL REGISTRATION: Clinicaltrial.govNCT02297776, 2014-11-21.

The Role of Inflammatory Cytokines in Cardiac Arrest.

INTRODUCTION: Post-cardiac arrest syndrome (PCAS) is characterized by systemic ischemia/reperfusion injury, anoxic brain injury, and post-arrest myocardial dysfunction superimposed on a precipitating pathology. The role of inflammatory cytokines in cardiac arrest remains unclear. AIMS: We aimed to describe, with an emphasis on clinical applications, what is known about the role of inflammatory cytokines in cardiac arrest. DATA SOURCES: A PubMed literature review was performed for relevant articles. Only articles in English that studied cytokines in patients with cardiac arrest were included. RESULTS: Cytokines play a crucial role in the pathogenesis of PCAS. Following cardiac arrest, the large release of circulating cytokines mediates the ischemia/reperfusion injury, brain dysfunction, and myocardial dysfunction seen. Interleukins, tumor necrosis factor, and matrix metalloproteinases all play a unique prognostic role in PCAS. High levels of inflammatory cytokines have been associated with mortality and/or poor neurologic outcomes. Interventions to modify the systemic inflammation seen in PCAS continue to be heavily studied. Currently, the only approved medical intervention for comatose patients following cardiac arrest is targeted temperature management. Medical agents, including minocycline and sodium sulfide, have demonstrated promise in animal models. CONCLUSIONS: The role of inflammatory cytokines for both short- and long-term outcomes is an important area for future investigation.

Associations between early intra-arrest blood acidaemia and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study.

BACKGROUND: Resuscitation guidelines list acidaemia as a potentially reversible cause of cardiac arrest without specifying the threshold defining acidaemia. We examined the association between early intra-arrest arterial blood gas (ABG) data and outcomes of in-hospital cardiac arrest (IHCA). METHODS: This single-centred retrospective study reviewed patients with IHCA between 2006 and 2015. Early intra-arrest ABG data were measured within 10 min of initiating cardiopulmonary resuscitation. The ABG analysis included measurements of blood pH, PaCO2, and HCO3-. RESULTS: Among the 1065 included patients, 60 (5.6%) achieved neurologically intact survival. Mean blood pH was 7.2. Mean PaCO2 and HCO3- levels were 59.7 mmHg and 22.1 mmol/L, respectively. A blood pH of 7.2 was identified by a generalised additive models plot to define severe acidaemia. The PaCO2 level was higher in patients with severe acidaemia (mean: 74.5 vs. 44.1 mmHg) than in those without. Multivariable logistic regression analyses indicated that blood pH > 7.2 was associated with a favourable neurological recovery (odds ratio [OR]: 2.79, 95% confidence interval [CI]: 1.43-5.46; p-value = 0.003) and blood pH was positively associated with survival at hospital discharge (OR: 5.80, 95% CI: 1.62-20.69; p-value = 0.007). CONCLUSION: Early intra-arrest blood pH was associated with IHCA outcomes, while levels of PaCO2 and HCO3- were not. A blood pH of 7.2 could be used as the threshold defining severe acidaemia during arrest and help profile patients with IHCA. Innovative interventions should be developed to improve the outcomes of patients with severe acidaemia, such as novel ventilation methods.

Protective effects of therapeutic hypothermia on renal injury in an asphyxial cardiac arrest rat model.

Cardiac arrest (CA) is a leading cause of mortality worldwide. Most of post-resuscitation related deaths are due to post-cardiac arrest syndrome (PCAS). After cardiopulmonary resuscitation (CPR), return of spontaneous circulation (ROSC) leads to renal ischemia-reperfusion injury, also known as PCAS. Many studies have focused on brain and heart injuries after ROSC, but renal failure has largely been ignored. Therefore, we investigated the protective effects of therapeutic hypothermia (TH) on asphyxial CA-induced renal injury in rats. Thirty rats were randomly divided into five groups: 1) the control group (sham); 2) the normothermic CA (nor.); 3) a normothermic CA group that received TH immediately within 2 h after CPR (Hypo. 2 hrs); 4) a normothermic CA group that received TH within 4 h after CPR (Hypo. 4 hrs); and 5) a normothermia CA group that received TH within 6 h after CPR (Hypo. 6 h). One day after CPR, all rats were sacrificed. Compared with the normothermic CA group, the TH groups demonstrated significantly increased survival rate (P < 0.05); decreased serum blood urea nitrogen, creatinine, and lactate dehydrogenase levels; and lower histological damage degree and malondialdehyde concentration in their renal tissue. Terminal deoxynucleotidyl transferase dUTP nick end labeling stain revealed that the number of apoptotic cells significantly decreased after 4 h and 6 h of TH compared to the results seen in the normothermic CA group. Moreover, TH downregulated the expression of cyclooxygenase-2 in the renal cortex compared to the normothermic CA group one day after CPR. These results suggest that TH exerts anti-apoptotic, anti-inflammatory, and anti-oxidative effects immediately after ROSC that protect against renal injury.

Circulating Levels of Brain-Enriched MicroRNAs Correlate with Neuron Specific Enolase after Cardiac Arrest-A Substudy of the Target Temperature Management Trial.

Outcome prognostication after cardiac arrest (CA) is challenging. Current multimodal prediction approaches would benefit from new biomarkers. MicroRNAs constitute a novel class of disease markers and circulating levels of brain-enriched ones have been associated with outcome after CA. To determine whether these levels reflect the extent of brain damage in CA patients, we assessed their correlation with neuron-specific enolase (NSE), a marker of brain damage. Blood samples taken 48 h after return of spontaneous circulation from two groups of patients from the Targeted Temperature Management trial were used. Patients were grouped depending on their neurological outcome at six months. Circulating levels of microRNAs were assessed by sequencing. NSE was measured at the same time-point. Among the 673 microRNAs detected, brain-enriched miR9-3p, miR124-3p and miR129-5p positively correlated with NSE levels (all p < 0.001). Interestingly, these correlations were absent when only the good outcome group was analyzed (p > 0.5). Moreover, these correlations were unaffected by demographic and clinical characteristics. All three microRNAs predicted neurological outcome at 6 months. Circulating levels of brain-enriched microRNAs are correlated with NSE levels and hence can reflect the extent of brain injury in patients after CA. This observation strengthens the potential of brain-enriched microRNAs to aid in outcome prognostication after CA.

Serum Magnesium Levels and Neurological Outcomes in Patients Undergoing Targeted Temperature Management After Cardiac Arrest.

INTRODUCTION: Magnesium plays a neuroprotective role at the physiologic level, but its neuroprotective role in patients undergoing targeted temperature management for cardiac arrest is not well established. We performed multiple logistic regression analysis to evaluate whether magnesium levels can predict neurological outcomes in patients undergoing targeted temperature management after cardiac arrest. METHODS: We retrospectively investigated data on 86 patients who had undergone targeted temperature management after cardiac arrest between December 2015 and November 2017. The primary outcome was to determine whether magnesium levels predict unfavorable neurological outcomes for patients with return of spontaneous circulation after targeted temperature management. Cerebral Performance Category 3, 4, or 5 indicated unfavorable neurological outcomes. We performed multiple logistic regression to evaluate the primary outcome, adjusting for the time to return of spontaneous circulation, motor score of the Glasgow Coma Scale, first-recorded cardiac rhythm, pH, and magnesium levels. RESULTS: Of the 86 patients, 58 had unfavorable neurological outcomes. The mean hospital stay was 19 days. Multivariable analysis indicated that magnesium levels were not associated with an unfavorable neurological outcome. In contrast, a time to return of spontaneous circulation greater than 30 minutes and Glasgow Coma Scale motor score of 1 were significantly associated with an unfavorable neurological outcome. DISCUSSION: Magnesium levels were not associated with an unfavorable neurological outcome according to multivariable analysis. We found that a time to return of spontaneous circulation greater than 30 minutes and Glasgow Coma Scale motor score of 1 might predict an unfavorable neurological outcome.

Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study.

BACKGROUND: Studies examining the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes have reported conflicting results. Our objective was to test the hypothesis that early postresuscitation hyperoxia is associated with poor neurological outcome. METHODS: This was a multicenter prospective cohort study. We included adult patients with cardiac arrest who were mechanically ventilated and received targeted temperature management after return of spontaneous circulation. We excluded patients with cardiac arrest caused by trauma or sepsis. Per protocol, partial pressure of arterial oxygen (Pao2) was measured at 1 and 6 hours after return of spontaneous circulation. Hyperoxia was defined as a Pao2 >300 mm Hg during the initial 6 hours after return of spontaneous circulation. The primary outcome was poor neurological function at hospital discharge, defined as a modified Rankin Scale score >3. Multivariable generalized linear regression with a log link was used to test the association between Pao2 and poor neurological outcome. To assess whether there was an association between other supranormal Pao2 levels and poor neurological outcome, we used other Pao2 cut points to define hyperoxia (ie, 100, 150, 200, 250, 350, 400 mm Hg). RESULTS: Of the 280 patients included, 105 (38%) had exposure to hyperoxia. Poor neurological function at hospital discharge occurred in 70% of patients in the entire cohort and in 77% versus 65% among patients with versus without exposure to hyperoxia respectively (absolute risk difference, 12%; 95% confidence interval, 1-23). Hyperoxia was independently associated with poor neurological function (relative risk, 1.23; 95% confidence interval, 1.11-1.35). On multivariable analysis, a 1-hour-longer duration of hyperoxia exposure was associated with a 3% increase in risk of poor neurological outcome (relative risk, 1.03; 95% confidence interval, 1.02-1.05). We found that the association with poor neurological outcome began at ≥300 mm Hg. CONCLUSIONS: Early hyperoxia exposure after resuscitation from cardiac arrest was independently associated with poor neurological function at hospital discharge.

Optimal Arterial Blood Oxygen Tension in the Early Postresuscitation Phase of Extracorporeal Cardiopulmonary Resuscitation: A 15-Year Retrospective Observational Study.

OBJECTIVES: Hyperoxia could lead to a worse outcome after cardiac arrest. Few studies have investigated the impact of oxygenation status on patient outcomes following extracorporeal cardiopulmonary resuscitation. We sought to delineate the association between oxygenation status and neurologic outcomes in patients receiving extracorporeal cardiopulmonary resuscitation. DESIGN: Retrospective analysis of a prospective extracorporeal cardiopulmonary resuscitation registry database. SETTING: An academic tertiary care hospital. PATIENTS: Patients receiving extracorporeal cardiopulmonary resuscitation between 2000 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 291 patients were included, and 80.1% were male. Their mean age was 56.0 years. The arterial blood gas data employed in the primary analysis were recorded from the first sample over the first 24 hours in the ICUs after return of spontaneous circulation. The mean PaO2 after initiation of venoarterial extracorporeal membrane oxygenation was 178.0 mm Hg, and the mean PaO2/FIO2 ratio was 322.0. Only 88 patients (30.2%) demonstrated favorable neurologic status at hospital discharge. Multivariate logistic regression analysis indicated that PaO2 between 77 and 220 mm Hg (odds ratio, 2.29; 95% CI, 1.01-5.22; p = 0.05) and PaO2/FIO2 ratio between 314 and 788 (odds ratio, 5.09; 95% CI, 2.13-12.14; p < 0.001) were both positively associated with favorable neurologic outcomes. CONCLUSIONS: Oxygenation status during extracorporeal membrane oxygenation affects neurologic outcomes in patients receiving extracorporeal cardiopulmonary resuscitation. The PaO2 range of 77 to 220 mm Hg, which is slightly narrower than previously defined, seems optimal. The PaO2/FIO2 ratio was also associated with outcomes in our analysis, indicating that both PaO2 and the PaO2/FIO2 ratio should be closely monitored during the early postcardiac arrest phase for postextracorporeal cardiopulmonary resuscitation patients.

Study of the Effects of Epinephrine on Cerebral Oxygenation and Metabolism During Cardiac Arrest and Resuscitation by Hyperspectral Near-Infrared Spectroscopy.

OBJECTIVES: Epinephrine is routinely administered to sudden cardiac arrest patients during resuscitation, but the neurologic effects on patients treated with epinephrine are not well understood. This study aims to assess the cerebral oxygenation and metabolism during ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation, and epinephrine administration. DESIGN: To investigate the effects of equal dosages of IV epinephrine administrated following sudden cardiac arrest as a continuous infusion or successive boluses during cardiopulmonary resuscitation, we monitored cerebral oxygenation and metabolism using hyperspectral near-infrared spectroscopy. SETTINGS: A randomized laboratory animal study. SUBJECTS: Nine healthy pigs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our study showed that although continuous epinephrine administration had no significant impact on overall cerebral hemodynamics, epinephrine boluses transiently improved cerebral oxygenation (oxygenated hemoglobin) and metabolism (cytochrome c oxidase) by 15% ± 6.7% and 49% ± 18%, respectively (p < 0.05) compared with the baseline (untreated) ventricular fibrillation. Our results suggest that the effects of epinephrine diminish with successive boluses as the impact of the third bolus on brain oxygen metabolism was 24.6% ± 3.8% less than that of the first two boluses. CONCLUSIONS: Epinephrine administration by bolus resulted in transient improvements in cerebral oxygenation and metabolism, whereas continuous epinephrine infusion did not, compared with placebo. Future studies are needed to evaluate and optimize the use of epinephrine in cardiac arrest resuscitation, particularly the dose, timing, and mode of administration.

Pharmacokinetic effects of endotracheal, intraosseous, and intravenous epinephrine in a swine model of traumatic cardiac arrest.

INTRODUCTION: Limited prospective data exist regarding epinephrine's controversial role in managing traumatic cardiac arrest (TCA). This study compared the maximum concentration (Cmax), time to maximum concentration (Tmax), plasma concentration over time, return of spontaneous circulation (ROSC), time to ROSC, and odds of ROSC of epinephrine administered by the endotracheal (ETT), intraosseous (IO), and intravenous (IV) routes in a swine TCA model. METHODS: Forty-nine Yorkshire-cross swine were assigned to seven groups: ETT, tibial IO (TIO), sternal IO (SIO), humeral IO (HIO), IV, CPR with defibrillation (CPRD), and CPR only. Swine were exsanguinated 31% of their blood volume and cardiac arrest induced. Chest compressions began 2 min post-arrest. At 4 min post-arrest, 1 mg epinephrine was administered, and blood specimens collected over 4 min. Resuscitation continued until ROSC or 30 min elapsed. RESULTS: The Cmax of IV epinephrine was significantly higher than the TIO group (P = 0.049). No other differences in Cmax, Tmax, ROSC, and time to ROSC existed between the epinephrine groups (P > 0.05). Epinephrine levels were detectable in two of seven ETT swine. No significant difference in ROSC existed between the epinephrine groups and CPRD group (P > 0.05). Significant differences in ROSC existed between all groups and the CPR only group (P < 0.05). No significant differences in odds of ROSC were noted. CONCLUSIONS: The pharmacokinetics of IV, HIO, and SIO epinephrine were comparable. Endotracheal epinephrine absorption was highly variable and unreliable compared to IV and IO epinephrine. Epinephrine appeared to have a lesser role than volume replacement in resuscitating TCA.

On-the-Scene Hyaluronan and Syndecan-1 Serum Concentrations and Outcome after Cardiac Arrest and Resuscitation.

BACKGROUND: It is not predictable which patients will develop a severe inflammatory response after successful cardiopulmonary resuscitation (CPR), also known as "postcardiac arrest syndrome." This pathology affects only a subgroup of cardiac arrest victims. Whole body ischemia/reperfusion and prolonged shock states after return of spontaneous circulation (ROSC) may both contribute to this devastating condition. The vascular endothelium with its glycocalyx is especially susceptible to initial ischemic damage and may play a detrimental role in the initiation of postischemic inflammatory reactions. It is not known to date if an immediate early damage to the endothelial glycocalyx, detected by on-the-scene blood sampling and measurement of soluble components (hyaluronan and syndecan-1), precedes and predicts multiple organ failure (MOF) and survival after ROSC. METHODS: 15 patients after prehospital resuscitation were included in the study. Serum samples were collected on the scene immediately after ROSC and after 6 h, 12 h, 24 h, and 48 h. Hyaluronan and syndecan-1 were measured by ELISA. We associated the development of multiple organ failure and 30-day survival rates with these serum markers of early glycocalyx damage. RESULTS: Immediate serum hyaluronan concentrations show significant differences depending on 30-day survival. Further, the hyaluronan level is significantly higher in patients developing MOF during the initial and intermediate resuscitation period. Also, the syndecan-1 levels are significantly different according to MOF occurrence. CONCLUSION: Serum markers of glycocalyx shedding taken immediately on the scene after ROSC can predict the occurrence of multiple organ failure and adverse clinical outcome in patients after cardiac arrest.

Fingolimod Plays Role in Attenuation of Myocardial Injury Related to Experimental Model of Cardiac Arrest and Extracorporeal Life Support Resuscitation.

BACKGROUND: Sudden cardiac arrest is a major global health concern, and survival of patients with ischemia-reperfusion injury is a leading cause of myocardial dysfunction. The mechanism of this phenomenon is not well understood because of the complex pathophysiological nature of the disease. Aim of the study was to investigate the cardioprotective role of fingolimod in an in vivo model of cardiac arrest and resuscitation. METHODS: In this study, an in vivo rat model of cardiac arrest using extracorporeal membrane oxygenation resuscitation monitored by invasive hemodynamic measurement was developed. At the beginning of extracorporeal life support (ECLS), animals were randomly treated with fingolimod (Group A, n = 30) or saline (Group B, n = 30). Half of the animals in each group (Group A1 and B1, n = 15 each) were sacrificed after 1 h, and the remaining animals (Group A2 and B2) after 24 h of reperfusion. Blood and myocardial tissues were collected for analysis of cardiac features, inflammatory biomarkers, and cell signaling pathways. RESULTS: Treatment with fingolimod resulted in activation of survival pathways resulting into reduced inflammation, myocardial oxidative stress and apoptosis of cardiomyocytes. This led to significant improvement in systolic and diastolic functions of the left ventricle and improved contractility index. CONCLUSIONS: Sphingosine1phosphate receptor activation with fingolimod improved cardiac function after cardiac arrest supported with ECLS. Present study findings strongly support a cardioprotective role of fingolimod through sphingosine-1-phosphate receptor activation during reperfusion after circulatory arrest.