Cardiac Arrest Group Research Articles

Sevoflurane Postconditioning Increases the Activities of Antioxidant Enzymes and Improves Spatial Learning and Memory after Cardiac Arrest in Rats

Background: Sevoflurane, as a novel volatile anesthetic with minimal pungency, low solubility, and less toxicity, is widely used in anesthetic practice. The purpose of this study was to investigate the effect of sevoflurane postconditioning on endogenous antioxidant status and spatial learning and memory ability after cardiac arrest (CA) and the potential underlying mechanisms.Methods: A rat model of CA was established by delivering an alternating current between the esophagus and chest wall to induce ventricular fibrillation. Animals were randomly divided into three groups: sham group (no CA), CA group, and CA+sevoflurane postconditioning (CA+SE) group. Sevoflurane postconditioning was achieved by administration of 2.5% sevoflurane for 60 min after resuscitation. The spatial learning and memory ability of rats was measured by the Morris water maze. The antioxidant enzymes activities were assessed at 4 hours, 1 day and 8 days after resuscitation. Moreover, the expressions of hippocampal proteins which could serve as memory enhancement biomarkers including growth-associated protein-43 (GAP-43), postsynaptic density-95 (PSD-95) and the transcription factor c-jun/activator protein-1 (AP-1), were detected at 8 days after resuscitation.Results: We found that CA significantly decreased the ability of spatial learning and memory in contrast to the sham controls. However, sevoflurane postconditioning significantly increased survival rate and antioxidant enzyme activities as well as ameliorated the spatial learning and memory deficits induced by CA. Furthermore, sevoflurane postconditioning regulated hippocampal memory enhancement proteins.Conclusions: Postconditioning with sevoflurane improved learning and memory deficits in a CA model possibly due to the reduction of oxidative stress and up-regulation of the memory enhancement biomarkers in hippocampus. Citation: Zhi Ye, Zi-Yu Zhou, Na Wang, Ping-Ping Xia, E Wang, Qu-Lian Guo. Sevoflurane postconditioning increases the activities of antioxidant enzymes and improves spatial learning and memory after cardiac arrest in rats. J Anesth Perioper Med 2016; 3: 149-159. doi: 10.24015/JAPM.2016.0020This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Inhibiting High-Mobility Group Box 1 (HMGB1) Attenuates Inflammatory Cytokine Expression and Neurological Deficit in Ischemic Brain Injury Following Cardiac Arrest in Rats.

Cardiac arrest (CA), if untreated for more than 5min, can induce severe brain damage, the underlying mechanism of which is still unclear. Previous studies have indicated that high-mobility group box 1 (HMGB1), a nuclear protein implicated in several inflammatory disorders, is involved in the inflammatory processes following brain ischemia. However, the role of HMGB1 in brain dysfunction after CA is yet to be determined. In a rat CA model, HMGB1 protein expression was higher at 1, 3, and 7days post-CA, compared to that in naïve and sham-treated rats. Following injection of HMGB1 antibody (anti-HMGB1) into the cerebral ventricles, neurological deficit scores were significantly decreased in the CA group as compared to that in the naïve and sham group. Nissl staining showed significant neuronal loss in the hippocampal CA1 region following CA, which was significantly attenuated by anti-HMGB1-treatment (10 and 50μg) in comparison with the vehicle-injected control. CA induced a significant increase in the levels of the cytokine interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in the hippocampus as revealed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Treatment with anti-HMGB1 significantly inhibited IL-1β and TNF-α expression. Our study suggests that HMGB1 contributes significantly to CA-induced brain dysfunction and that inhibiting HMGB1 function and expression may be an effective therapeutic approach to CA-induced ischemic brain injury.

Reduced long-term memory in a rat model of 8minutes ventricular fibrillation cardiac arrest: a pilot trial.

BackgroundEvaluating beneficial effects of potential protective therapies following cardiac arrest in rodent models could be enhanced by exploring behavior and cognitive functions. The Morris Water Maze is a well-known cognitive paradigm to test spatial learning and memory.ResultsBehavioral testing with the Morris Water Maze in Sprague–Dawley rats (300 ± 25 g) resuscitated after 8 min of ventricular fibrillation cardiac arrest was carried out 5 and 12 weeks after cardiac arrest (CA) and compared to results of naïve rats (Control).At 5 weeks, within each group latency time to reach the hidden platform (reflecting spatial learning) decreased equally from day 1 to 4 (CA: 105.6 ± 8.2 vs. 8.9 ± 1.2 s, p < 0.001; Control: 75.5 ± 13.2 vs. 17.1 ± 4.5, p < 0.001) with no differences between groups (p = 0.138). In the probe trial 24 h after the last trial, time spent in the target sector (reflecting memory recall) within each group was significantly longer (CA: 25 ± 1.3; Control: 24.7 ± 2.5 s) than in each of the three other sectors (CA: 7.7 ± 0.7, 14.3 ± 2.5, 8.4 ± 0.8 and Control: 7.8 ± 1.2, 11.7 ± 1.5, 10.3 ± 1.6 s) but with no significantly differences between groups. Seven days later (reflecting memory retention), control group animals remained significantly longer in the target sector compared to every other sector, whereas the cardiac arrest group animals did not. Even 12 weeks after cardiac arrest, the single p values showed that the control animals displayed a trend to perform better than the resuscitated animals.ConclusionsMemory recall was impaired early after 8 min of ventricular fibrillation cardiac arrest and might be a more valuable tool for cognitive testing than learning recall after global ischemia due to cardiac arrest.

Effect of heparin on mesenteric microcirculation in a rabbit model of cardiac arrest and cardiopulmonary resuscitation

Objective To investigate the effect of heparin on mesenteric microcirculation in a rabbit model of cardiac arrest and cardiopulmonary resuscitation (CPR). Methods Thirty-two New Zealand white rabbits of both sexes, weighing 2.0-2.5 kg, were randomly divided into 3 groups using a random number table: control group (group C, n=8), cardiac arrest and CPR group (group CA/R, n=12), and heparin group (group H, n=12). Cardiac arrest was induced by clamping the tracheal tube, and 5 min later CPR was started.Heparin 0.5 mg/kg was injected intravenously at the onset of CPR in group H. The mean arterial pressure (MAP) and heart rate (HR) were recorded before cardiac arrest (T0), immediately after recovery of spontaneous circulation(T1), and at 30 min and 1 h of recovery of spontanenous circulation (T2, 3). A microvessel 15-20 μm in diameter was obtained from the mesentery to record the blood flow velocity, and the K value of microthrombus was calculated. Results Compared with group C, MAP at T1 and HR at T1, 2 were significantly decreased, and the microvascular blood flow velocity was decreased in CA/R and H groups (P<0.05). Compared with group CA/R, no significant change was found in MAP and HR, the microvascular blood flow velocity was significantly increased, and the K value of microthrombus was decreased in group H (P<0.05). Conclusion Heparin can accelerate microvascular blood flow velocity in the mesentery, reduce formation of microthrombus, and improve mesenteric microcirculation in a rabbit model of cardiac arrest and CPR. Key words: Heparin; Microcirculation; Heart arrest; Cardiopulmonary resuscitation

Effect of donor cardiac arrest and arrest duration on outcomes of lung transplantation.

Limited data are available about lung transplantation (LTx) from donors suffering cardiac arrest (CA) prior to actual donation. A retrospective analysis of LTx performed between January 2007 and September 2012 was done with the focus on CA in donors. The recipients were grouped depending on the history of donor CA and CA duration (downtime) as: No cardiac arrest ("NoCA"), CA downtime less than 20 min ("CA < 20"), and CA downtime equal to or more than 20 min ("CA > 20"). Early and mid-term outcomes after LTx were compared among the three groups. A total of 237 LTx were performed during the study period. One hundred eighty-eight patients received organs from "NoCA" donors, 25 from "CA < 20" donors, and 24 patients from "CA > 20" donors. There was a trend toward better overall cumulative survival in both CA groups (log rank p = 0.076) whereas the survival in the "CA > 20" group was significantly better than in the "NoCA" group in the subgroup analysis (log rank p = 0.045). Freedom from bronchiolitis obliterans syndrome (BOS) also increased with increase in CA duration, although it did not reach statistical significance. Transplantation of lungs from donors with a history of CA is safe and feasible. Longer duration of cardiac arrest may improve the outcomes after the LTx in terms of survival and freedom from BOS.

PD98059 Protects Brain against Cells Death Resulting from ROS/ERK Activation in a Cardiac Arrest Rat Model.

The clinical and experimental postcardiac arrest treatment has not reached therapeutic success. The present study investigated the effect of PD98059 (PD) in rats subjected to cardiac arrest (CA)/cardiopulmonary resuscitation (CPR). Experimental rats were divided randomly into 3 groups: sham, CA, and PD. The rats except for sham group were subjected to CA for 5 min followed by CPR operation. Once spontaneous circulation was restored, saline and PD were injected in CA and PD groups, respectively. The survival rates and neurologic deficit scores (NDS) were observed, and the following indices of brain tissue were evaluated: ROS, MDA, SOD, p-ERK1/2/ERK1/2, caspase-3, Bax, Bcl-2, TUNEL positive cells, and double fluorescent staining of p-ERK/TUNEL. Our results indicated that PD treatment significantly reduced apoptotic neurons and improved the survival rates and NDS. Moreover, PD markedly downregulated the ROS, MDA, p-ERK, and caspase-3, Bax and upregulated SOD and Bcl-2 levels. Double staining p-ERK/TUNEL in choroid plexus and cortex showed that cell death is dependent on ERK activation. The findings in present study demonstrated that PD provides neuroprotection via antioxidant activity and antiapoptosis in rats subjected to CA/CPR.

Carbon Monoxide Improves Neurologic Outcomes by Mitochondrial Biogenesis after Global Cerebral Ischemia Induced by Cardiac Arrest in Rats.

Mitochondrial dysfunction contributes to brain injury following global cerebral ischemia after cardiac arrest. Carbon monoxide treatment has shown potent cytoprotective effects in ischemia/reperfusion injury. This study aimed to investigate the effects of carbon monoxide-releasing molecules on brain mitochondrial dysfunction and brain injury following resuscitation after cardiac arrest in rats. A rat model of cardiac arrest was established by asphyxia. The animals were randomly divided into the following 3 groups: cardiac arrest and resuscitation group, cardiac arrest and resuscitation plus carbon monoxide intervention group, and sham control group (no cardiac arrest). After the return of spontaneous circulation, neurologic deficit scores (NDS) and S-100B levels were significantly decreased at 24, 48, and 72 h, but carbon monoxide treatment improved the NDS and S-100B levels at 24 h and the 3-day survival rates of the rats. This treatment also decreased the number of damaged neurons in the hippocampus CA1 area and increased the brain mitochondrial activity. In addition, it increased mitochondrial biogenesis by increasing the expression of biogenesis factors including peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor-1, nuclear respiratory factor-2 and mitochondrial transcription factor A. Thus, this study showed that carbon monoxide treatment alleviated brain injury after cardiac arrest in rats by increased brain mitochondrial biogenesis.

Controversies on Hypothermia in Cardiac Arrest

The American Heart Association guidelines on resuscitation have recently come out. Hypothermia between 32°C and 34°C was recommended as a Class I indication in the 2010 guidelines for shockable rhythms. The resuscitation council referred to two articles that were published in NEJM in 2002 for this robust recommendation. The Targeted Temperature Management (TTM) trial that came out in 2013 had contrary findings compared with those of these previous articles. Despite the results of the TTM trial, the resuscitation council preferred to keep the recommendation level as Class I rather than lowering it (1). Although it has been retained as Class I, the recommended body temperature recommended is in the range of 32°C–36°C. This might be related to the intention of not stepping back rather than scientific concerns. Taking a glance at pioneering articles that underpinned the 2010 guidelines for hypothermia may lead to a comprehensive insight on the issue. The first trial was a small study by Bernard et al. (2). They conducted a quasi-randomized trial in patients who had a spontaneous return of circulation following a cardiac arrest due to ventricular fibrillation (VF). The intervention was cooling the patients at 33°C for 12 hours (h). The favoring neurological outcome was 49% in intervention group and 26% in control group (p=0.046). The second trial was by the “Hypothermia After Cardiac Arrest Group,” in which over 250 patients were enrolled, and this trial had a larger sample size than the first (3). The authors studied hypothermia defined as 32°C–34°C for 24 h in patients who had return of spontaneous circulation (ROSC) following VF. Favoring neurological outcome assessed by the Pittsburgh cerebral performance scale was reported to be 55% in the intervention group and 39% in the control group (p=0.009). The findings of these two trials have been cited for stating hypothermia as a Class I recommendation in patients who have ROSC following VF arrest. Robust data regarding hypothermia in cardiac arrest patients has been presented by the TTM trial that came out in 2013 (4). It had been conducted in 36 intensive care units in Europe and Australia and has recruited over 900 patients. The TTM trial compared 33°C vs. 36°C that can also be defined as normothermia. The authors recruited all patients either with shockable or non-shockable rhythms except unwitnessed patients with an initial rhythm of asystole. Poor neurological outcome (Modified Rankin Scale score of 4–6) was the same in both groups (52% vs 52%, respectively) and was 54% in the hypothermia group and 52% in the control group when assessed by the Cerebral Performance Category of 3–5 (p=0.78). Despite the lack of subgroup analysis reporting the neurological outcome for shockable rhythms, mortality rates were 40.8% in the hypothermia group and 39.7% in the control group for patients who had an initial shockable rhythm. The detailed analysis of the studies and meta-analysis on the issue are available in the current issue of the Eurasian Journal of Emergency Medicine (5). A classical phenomenon has been posed in hypothermia trials that studies with a small sample size are prone to misleading effects of random error and chance factor. Random error indicates the effect of heterogeneity factor on the results and findings of small studies. Studies with small sample sizes might have fluctuating results and will be closer to the real values when more patients are recruited; this can be explained by the law of large numbers. The first two trials composed the basics of the recommendation in 2010 had approximately 350 patients, and the TTM trial brought out the unfavorableness of performing robust recommendations using the findings of small trials rather than waiting for more powered ones.

Effects of mitochondrial division inhibitor on neurological function and neuronal apoptosis in rats after cardiopulmonary resuscitation

To investigate the effects of mitochondrial division inhibitor 1 (mdivi-1) in rats after cardiopulmonary resuscitation (CPR) and its mechanism. Fifty Sprague-Dawley (SD) rats were randomly (random number table) divided into sham group (n = 8), cardiac arrest (CA) model group (n = 14), dimethyl sulfoxide post-treatment control group (DMSO group, n = 14), and mdivi-1 post-treatment group (mdivi-1 group, n = 14). Asphyxial CA was reproduced in animals, and they were resuscitated by CPR. In the mdivi-1 group or DMSO group, the animals were given mdivi-1 (1.2 mg/kg) or DMSO (0.1%) intravenously after restoration of spontaneous circulation ( ROSC ). The neurological functions were assessed using neurological deficit score (NDS) determined at 24, 48 and 72 hours after CPR. The brain tissues were harvested at 72 hours after CPR. The histopathologic changes were assessed by hematoxylin and eosin (HE) staining, and the normal neuron was counted. The neuronal apoptosis was assessed with terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and the expressions of cytochrome C (Cyt-C) protein in mitochondria and cytoplasm from hippocampus were determined by Western Blot. NDS in all experiment groups was gradually increased after CPR, and they were significantly lower than those of the sham group at 24, 48, and 72 hours (51.5 ± 3.7 vs. 80.0 ± 0.0, 59.3 ± 3.6 vs. 80.0 ± 0.0, 66.7 ± 2.6 vs. 80.0 ± 0.0, all P < 0.05). The number of normal pyramidal neurons in the hippocampal CA1 region was markedly reduced (cells/HP: 4.4 ± 1.1 vs. 23.1 ± 4.0, P < 0.05), the apoptotic index was significantly increased [(86.9 ± 6.9)% vs. (3.4 ± 0.8)%, P < 0.05], the expressions of Cyt-C in mitochondria were significantly decreased (A value: 0.46 ± 0.18 vs. 1.00 ± 0.00, P < 0.05), and the expressions of Cyt-C in cytoplasm were significantly up-regulated (A value: 6.65 ± 0.21 vs. 1.00 ± 0.00, P < 0.05). Compared with the CA group, NDS at 24 hours and 48 hours in mdivi-1 group was slightly increased (55.2 ± 3.3 vs. 51.5 ± 3.7, 64.7 ± 2.4 vs. 59.3 ± 3.6, both P > 0.05), and it was significantly increased at 72 hours (74.5 ± 2.3 vs. 66.7 ± 2.6, P < 0.05), the number of normal pyramidal neurons in the hippocampal CA region was markedly increased (cells/HP: 16.2 ± 2.4 vs. 4.4 ± 1.1, P < 0.05), the apoptotic index was dramatically reduced [(42.3 ± 3.9 )% vs. (86.9 ± 6.9 )%, P < 0.05], the expressions of Cyt-C in mitochondria were significantly increased (A value: 0.83 ± 0.22 vs. 0.46 ± 0.18, P < 0.05), and the expressions of Cyt-C in cytoplasm were significantly decreased (A value: 3.84 ± 0.47 vs. 6.65 ± 0.21, P < 0.05). There was no statistically significant difference in above indexes between CA group and DMSO group. By inhibiting mitochondrial Cyt-C apoptotic pathway to reduce neuronal apoptosis in rats after CA-CPR, mdivi-1 can improve brain function after CPR.

Abstract 10900: Persistent Alterations in Energy Metabolism and Oxygen Consumption Following Cardiac Arrest

Introduction: Although metabolic problems after cardiac arrest (CA) have been postulated, the actual measurement of metabolic alterations after CA remain undescribed. The measurement of oxygen extraction (VCO2), carbon dioxide excretion (VCO2), and respiratory quotient (RQ), reflect the energy metabolism and may provide insight into the post-arrest metabolism. Objective: To investigate metabolism alterations after CA, which may be detected via changes in VCO2, VO2, and RQ. Secondarily to test whether it is affected by therapeutic temperature management (TTM) Methods: Sixteen male rats underwent a protocol for 10 minutes of asphyxial CA and return of spontaneous circulation (ROSC). Three groups were compared: Group1: controls (no-CA, n=5), group2: CA (n=6), and group3: CA with TTM (n=5). Within the TTM group, the body was cooled to 33 °C. Capnography was recorded and O2 extraction was measured for 120min to measure VCO2 and VO2. RQ was the ratio of VCO2/VO2. Results: The post arrest VCO2 was 1.5 fold higher in the CA group than in the controls (17.3±2.2mL/kg/min versus 11.2±1.0mL/kg/min, p&lt;.01) in minutes 20 through 60. The VCO2 value in CA was normalized after 60min. VCO2 (12.5±1.3 mL/kg/min, p&lt;.01) in TTM-treated CA was significantly lower than untreated CA. The post arrest VO2 was greater in the CA group than in the controls, starting 15min after ROSC, and gradually increased to an extraction rate 2.1 fold higher (29.8±6.0mL/kg/min) than controls (14.1±1.6mL/kg/min, p&lt;.01). There were no differences in VO2 between TTM-treated and untreated CA. RQs in TTM-treated and untreated CA were significantly and persistently lower than controls (0.5±0.1, 0.5±0.1 vs. 0.9±0.1, p&lt;.01). Conclusions: VO2 in rats after CA was markedly elevated after ROSC and RQ decreased to extremely low levels. VCO2 showed some attenuation by TTM, however surprisingly TTM did not affect VO2 or RQ. These results suggest that profound alterations in oxygen extraction occur after CA and may be measured non-invasively in patients. The finding of a lowered RQ has not be described previously, appears to be driven by increased VO2, and may be due to non-CO2 generating oxygen utilization. If true, this may have great importance for mechanism, monitoring, and customized treatment of CA.

Abstract 18408: Cortical Spreading Depolarizations After Cardiac Arrest in an Asphyxial Rat Model

Introduction: Delayed neuronal cell death is observed following cardiac arrest (CA). The exact mechanisms remain unknown. Cortical spreading depolarization (CSD) is characterized by depolarization of neurons and glia cells, spreading as a wave that travels across the cortex. CSDs are known to occur in peri-infarct tissue and have been associated with poor outcome after stroke, and might contribute to the progression of neuronal injury after CA. Objective: To investigate if spontaneous CSDs occur during the post resuscitation period following CA, and to describe the characteristics of induced CSDs. Methods: Isoflurane-anesthetized Sprague-Dawley rats were randomized into one control group observed for 90 min (n=8), and two CA groups observed for 90 min (CA90min, n=7) and 360 min (CA360min, n=7), respectively, before data collection started. Animals underwent 8 min of asphyxial CA. Electrophysiological recordings were obtained over the right hemisphere through a burr hole. Potassium chloride (KCL) was applied onto the cortex through a separate burr hole in order to induce CSDs. Direct current recordings were gathered using an AgCl glass electrode. Induced abnormal CSDs were defined as CSDs with prolonged duration, low peak value, altered propagation speed and/or epileptiform discharges. Data collection (210 min) was divided into two periods: 1) In the 1 st period no stimulation was applied in order to detect spontaneous elicited CSDs. 2) In the 2 nd period KCl was applied. Results: Spontaneous CSDs were observed in one CA360min animal with prolonged CPR and time to return of spontaneous circulation of 298 sec. Significantly fewer CSDs were induced following KCl application in CA animals when compared with healthy controls (median(IQR) Control: 6(5-7) CA90min: 2(1-4) CA360min: 1(1-3), p&lt;0.05). Induced abnormal CSDs were seen in both CA groups but not in controls (control vs. CA90min p=0.004, control vs. CA360min p=0.054). KCl application elicited multiple CSDs in rapid succession in 50% of CA animals and none of the controls (p=0.052). Conclusion: CSDs can occur following prolonged CA and resuscitation, and may lead to additional neuronal injury. The appearance and number of induced CSDs were altered in CA animals in comparison with healthy controls.

Abstract 18424: Elective Cardiac Arrest in Isolated Aortic Valve Surgery: Comparison of Blood-cardioplegia versus HTK-Bretschneider Solution in 7005 Consecutive Patients

Introduction: Assessing the impact of HTK-Bretschneider solution versus blood-cardioplegia on short- and long-term outcome after isolated aortic valve replacement (AVR). Hypothesis: HTK-Bretschneider is not inferior to Blood-cardioplegia for isolated aortic valve replacement. Methods: Screening of our institutional database revealed 7290 consecutive patients who underwent AVR between 11/1994 and 06/2015. In the majority of patients (n=5998; 83%) antegrade infusion of htk-bretschneider solution (custodiol®) was used for elective cardiac arrest (Group A). Intermittent cold blood-cardioplegia was chosen in 1007 patients (14%; Group B). All preoperative risk-factors were considered for risk-factor analysis influencing outcome. Results: Early mortality was equal between the subgroups (p=0.22). Postoperative complications like pacemaker implantation (p=0.01) or low cardiac output were more likely to occur in group B (p=0.02). Overall long term survival was inferior for patients receiving elective cardiac arrest with cold blood cardioplegia (p&lt;0.001). Cox-regression identified age (HR: 1.063 ; p&lt;0.001), end stage renal disease (ESDR; HR:4.8; p&lt;0.001), history of PCI (HR: 1.3; p=0.03), active infective endocarditis (AIE; HR: 2.1; p&lt;0.001), neurological dysfunction (HR: 1.4; p=0.02), low ejection fraction (EF&lt;30%; HR: 2.5; p&lt;0.001), prior cardiac surgery (HR:1,5; p=0.02) and emergent surgical intervention (HR: 2.5; p&lt;0.001) being highly associated with long term survival and occurring more frequently in group B. Artificial low-risk and high-risk groups showed no differences in longevity depending on cardioplegic solutions (p=0.35). Conclusions: Blood-cardioplegia for elective cardiac arrest seems to be preferred when complex aortic valve surgery is expected. However, HTK-Bretschneider solution yields equivalent longevity to blood-cardioplegia, even after surgery demanding extended cross-clamp times.

Abstract 19510: Cytochrome C Levels in Post-cardiac Arrest Patients

Introduction: Cytochrome C is an essential component of the electron transport chain loosely bound to the inner mitochondrial membrane. Plasma Cytochrome C levels have shown to be elevated and associated with mortality in an animal model of cardiac arrest. Hypothesis: We hypothesized that cytochrome C levels would be elevated in post-cardiac arrest patients and higher in non-survivors as compared to survivors. Methods: We enrolled adult, out-of-hospital cardiac arrest patients with return of spontaneous circulation as part of the four-center COMICA study. Blood draws were performed after return of spontaneous circulation. We also performed blood draws in controls without acute illness. We measured plasma cytochrome C levels by applying the human cytochrome C Platinum ELISA (eBioceience, CA) kit to a MSD platform (Meso Scale Discovery, MD) to achieve greater dynamic range and sensitivity. We compared groups using the Wilcoxon Rank-Sum test. We used Spearman’s correlation coefficient (rs) to assess the correlation between Cytochrome C levels and initial lactate levels. Results: A total of 103 post-cardiac arrest patients and 40 controls had Cytochrome C levels measured. Cytochrome C levels were higher in post-cardiac arrest patients as compared to control subjects (2.18 nmol/L [quartiles: 0.74, 7.74] vs 0.20 nmol/L [0.03, 1.12], p &lt; 0.001, Figure 1). Fifty-five (53%) patients in the cardiac arrest group died. Patients who died had higher Cytochrome C levels as compared to survivors (3.66 nmol/L [1.40, 14.8] vs. 1.27 nmol/L [0.16, 2.37], p = 0.001, Figure 2). There was also a significant difference in Cytochrome C levels between patients with a good vs. a poor neurological outcome (1.3 nmol/L [0.3, 3.5] vs. 2.8 nmol/L [0.9, 9.9], p = 0.04). Cytochrome C levels were correlated with initial lactate levels (rs = 0.36, p = 0.001). Conclusion: Cytochrome C levels are elevated in post-cardiac arrest patients and non-survivors has higher levels.

Health-related quality of life at 2, 6 and 12 months after critical illness - lessons learnt from a nationwide follow-up of 4,500 ICU admissions

IntroductionThe development of intensive care medicine has led to improved survival of patients with complex illnesses and extensive injuries. Survivors are at risk of acquiring physical and functional deficits that may have negative effects on health-related quality of life (HRQoL). The significance of measuring HRQoL has been underlined by critical care researchers since poor HRQoL is associated with an adverse prognosis.ObjectiveThe aim of this work was to examine the development of HRQoL at 2, 6 and 12 months after ICU discharge in a mixed ICU patient population with an ICU-stay > 96 hrs.MethodsWe analysed admissions during 2008-2014 to 49 ICUs that submitted follow-up data to the Swedish Intensive Care Registry (SIR, http://www.icuregswe.org). HRQoL was measured using the Short Form 36 (SF36) questionnaire at 2, 6, and 12 months after discharge from ICU. SF36 domains, age, gender, illness severity on admission (SAPS3 probabilities) and length of ICU-stay were analysed for the entire cohort and for important diagnostic groups. SF36 scores were compared to an age- and gender-adjusted Swedish normal population. Differences in SF36 domains were analysed using non-parametric methods. Medians and interquartile ranges are presented.ResultsComplete SF36 responses were analysed for 4453, 4019 and 2515 admissions at 2, 6 and 12 months, respectively. HRQoL at 2 months in patients that subsequently were lost to follow-up was generally similar to those with follow-up, but they were younger, less ill and had shorter ICU-stay. Full longitudinal data with complete SF36 responses were obtained in 1438 patients [Age: 66 yrs. (57-73 yrs.), female gender: 37.2%, SAPS3 prob: 0.36 (0.19-0.55), ICU-stay: 7.0 days (4.9-11.5 days)]. SF36 improved over time in all domains (P < 0.001, Table), although some domains remained stable from 6 to 12 months. Patterns of recovery differed between important diagnostic groups (i.e. sepsis, out-of-hospital cardiac arrest, COPD, ARDS). A large proportion of patients (10-25% depending on SF36 domain) had HRQoL scores at 12 months which was below 2 standard deviations of the age- and gender-adjusted Swedish norm. The cardiac arrest group were among those with best, and the COPD group were among those with worst HRQoL at 12 months.ConclusionsHRQoL recovered over 12 months in critically ill patients with a prolonged ICU stay. Recovery varied between diagnostic groups and a large proportion of patients had markedly depressed HRQoL. These findings may have important implications for follow-up and care after critical illness.

Prevalence and outcomes of endotracheal intubation–related cardiac arrest in the ED

BackgroundEmergency endotracheal intubation–related cardiac arrest (CA) is not well documented. This study compares the clinical features and outcomes of intubation-related CA and other causes of inhospital CA. MethodsAll study patients were consecutive adults (≥18 years) who developed CA in the emergency department between January 2007 and December 2011. Emergent endotracheal intubation–related CA was defined as occurring within 20 minutes after successful intubation. Clinical variables were compared between patients with intubation-related CA and intubation-unrelated CA. The primary outcome was a good neurologic outcome defined as a Cerebral Performance Category score of 1 to 2. The secondary outcome was survival to hospital discharge. ResultsOf the 251 patients who developed CA, 41 were excluded due to trauma-related CA or “do-not-resuscitate” protocols, thereby leaving 210 patients. The prevalence of intubation-related CA was 23.3%, and the median duration between successful intubation and CA was 5.0 minutes (interquartile range, 2.0-9.5). Pulseless electrical activity was more commonly noted as the first arrest rhythm in the intubation-related CA group (75.5% vs 59.0%; P = .03) compared with patients with other causes of CA. However, the rates of good neurologic outcomes (14.3% vs 21.1%) and survival to discharge (34.7% vs 35.4%) were not significantly higher in intubation-related CA group (both P > .05). ConclusionEndotracheal intubation–related CA occurred higher than commonly recognized, and patient outcomes were not better than other causes of CA. These data highlight the importance of efforts to prevent intubation-related CA. However, further prospective larger study will be required to generalize this result.

NSC23766, A Specific Inhibitor of Rac1 GTPase, Attenuated Delayed Neuronal Cell Death and Cognitive Deficit in Rats with Cardiac Arrest

Background: Recent studies have implicated that inhibition of Rac1 GTPase protects the neuronal cells from cerebral ischemic injury, although its effects in a cardiac arrest (CA) global cerebral ischemia model have not been examined. The purpose of the current study was to examine the regulatory and functional role of the Rac1 in reactive oxygen species (ROS) generation and neuronal cell death/cognitive dysfunction following global cerebral ischemia in the rats.Methods: A rat model of CA was established by the delivery of alternating current between the esophagus and chest wall to induce ventricular fibrillation. Rats were randomly assigned to the following groups: 1) sham group, 2) CA group, 3) CA + NSC23766 group (NSC), and 4) CA + saline group. NSC23766 (50 μg, intracerebroventricular injection) or isotonic saline was administered 15 minutes before CA. Neurological function of rats after reperfusion was scored using the neurological deficit score evaluation method. Survival rates, neuronal counts, Rac1 activation, mitochondrial ROS formation and expression of thioredoxin2 (Trx2) and peroxiredoxin3 (Prx3) in the hippocampal CA1 region were assessed after reperfusion. Morris water maze task was used to quantify spatial learning and memory deficits after reperfusion.Results: NSC23766, the specific inhibitor of Rac1 GTPase, significantly attenuated neuronal damage and reduced the spatial learning and memory deficits associated with global cerebral ischemia induced by CA (P<0.05). Furthermore, NSC23766 exerted its neuroprotective function by decreasing the ROS generation (P<0.05). However, there was no significant difference of Trx2 and Prx3 protein expression in hippocampal CA1 region between the CA group and NSC group after 1 day reperfusion (P<0.05). Conclusions: Our findings suggested that NSC23766 not only ameliorated post-ischemic neuronal cell death, but also improved learning and memory deficits in a cerebral ischemia animal model through down-regulating ROS generation. Citation: Juan Liao, Chang Xu, Chang Liu, Na Wang, Guo-Qing Huang, Chang-Sheng Huang, et al. NSC23766, a specific inhibitor of Rac1 GTPase, attenuated delayed neuronal cell death and cognitive deficit in rats with cardiac arrest. J Anesth Perioper Med 2015; 2: 136-45. doi: 10.24015/JAPM.2015.0019This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Changes in Plasma Atrial and Brain Natriuretic Peptide Levels in Children Undergoing Surgical Isolated Atrial Septal Defect Closure.

Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels increase after cardiopulmonary bypass (CPB) in pediatric patients. However, the exact reason for the postoperative increase remains unclear. This study elucidated the perioperative changes in plasma natriuretic peptide levels in children undergoing surgical isolated atrial septal defect (ASD) closure. Between 2010 and 2012, 24 pediatric patients (median 7.1, range 2.7-15.7 years) underwent surgery for simple ASD using CPB under ventricular fibrillation (Group A, 16 patients) or under cardiac arrest (Group B, 8 patients). Natriuretic peptide levels were measured before surgery, on postoperative day 0, 1, 3, and at the first outpatient visit. The pulmonary to systemic blood flow ratio (Qp/Qs) was estimated by echocardiography using an index of right ventricle end-diastolic area. Preoperative natriuretic peptide levels positively correlated with the Qp/Qs. Plasma ANP levels peaked on postoperative day 0, and its values were higher in Group A than in Group B patients (p < 0.001). Plasma BNP levels increased significantly in both Groups on postoperative day 1, and its values were significantly greater in Group A than in Group B patients (p = 0.007). There was a weak negative correlation between the amount of postoperative increase in natriuretic peptide levels and the Qp/Qs. There was no appreciable difference in the acute postoperative clinical course and echocardiographic parameter on postoperative day 3 between Group A and B patients. In conclusion, acute postoperative natriuretic peptide levels after isolated ASD closure were multifactorial, and they might be unreliable for predicting clinical outcomes.

Out-of-hospital cardiac arrest from brain cause: epidemiology, clinical features, and outcome in a multicenter cohort*.

Although sudden cardiac death has been broadly studied, little is known on cerebrovascular events revealed by out-of-hospital cardiac arrest. We aimed to describe clinical features and prognosis of these patients and identify characteristics that could suggest a cerebrovascular etiology of the out-of-hospital cardiac arrest. Retrospective review (1999-2012) of databases of three regional referral ICU centers for out-of-hospital cardiac arrest. Patients admitted to ICU for management of successfully resuscitated out-of-hospital cardiac arrest. Patients were included when subarachnoid hemorrhage, intracranial hemorrhage, ischemic stroke, sub/epidural hematoma, or cerebral thrombophlebitis was identified as the primary cause of out-of-hospital cardiac arrest. Traumatic or infectious causes were excluded. Patients were compared with a group of out-of-hospital cardiac arrest of nonneurological origin. All medical records of the three prospective ICU databases, registered according to the Utstein style, were reviewed. Among 3,710 patients admitted for out-of-hospital cardiac arrest, 86 were included (mainly subarachnoid hemorrhage, n = 73). Prodromes were mostly neurological but falsely evoked a cardiac origin in six patients. Electrocardiogram displayed abnormalities in 64% of patients, with 23% of pseudoischemic pattern (ST-segment elevation or left bundle branch block). Mortality rate was 100%, with brain death as the leading cause. In comparison with the nonneurological out-of-hospital cardiac arrest group, female gender, onset of neurological prodromes, lack of other prodromes, initial nonshockable rhythm, and unspecific electrocardiogram repolarization abnormalities were independent predictive factors of a primary cerebrovascular etiology. When present, the combination of these elements displayed an area under the receiver operating characteristic curve of 0.86 (95% CI, 0.81-0.91). Presentation of cerebrovascular event complicated with out-of-hospital cardiac arrest may mimic coronary etiology, but several clinical elements may help to identify brain causes. Even if survival is null, the high proportion of brain deaths provides opportunity for organ donation.

Abstract 62: Preserved Cerebral Microcirculation After Cardiac Arrest in an Asphyxial Rat Model

Introduction: Cardiac arrest (CA) carries a dismal prognosis, mainly due to neurological injury. Studies have reported dysfunction of the sublingual microcirculation following cardiac arrest. The objective of the study was to investigate if this microcirculatory dysfunction is also present in the brain after cardiac arrest. Methods: Anesthetized, intubated, and ventilated, male Sprague-Dawley rats were randomized into two CA groups and two control groups and observed for 120 min or 360 min following return of spontaneous circulation (CA120min (n=8), Control120min (n=8), CA360min (n=8), and Control360min (n=8)). After ten minutes of ashpyxial induced CA animals were resuscitated using adrenalin and manual CPR. At the end of the observation period, cerebral microcirculation was evaluated by side stream dark field microscopy through a parietal craniotomy, and plasma samples were drawn for endothelial adhesion molecule and inflammatory marker analyses. Animals were monitored with invasive blood pressure, ECG and arterial blood gas samples throughout the study. Results: At the end of the observation period mean arterial pressure decreased significantly in the cardiac arrest groups being 55±12mmHg in the CA120min group and 51±9mmHg in the CA360min group compared to 85±8mmHg in the control groups, whereas PaCO2 was kept in the normal range and did not differ between groups. There was no difference between groups for total vessel density, perfused vessel density, proportion of perfused vessels, or microvascular flow index measured in the cerebral cortex. Plasma samples drawn 360 min after return of spontaneous circulation showed a significant increase in E-selectin, L-selectin, I-CAM1, IL-1β, IL-6, IL-10 and elastase compared to controls. Between the CA groups E-selectin and elastase showed an increase from 120 to 360 min after resuscitation (p&lt;0.007). Conclusion: Despite a significantly lower mean arterial pressure and elevated levels of soluble endothelial adhesion molecules and inflammatory cytokines, side stream dark field revealed no changes in the cerebral microcirculation in the early post resuscitation period.

The relationship between sarcoplasmic reticulum Ca(2+) modulation proteins and postresuscitation myocardial dysfunction

To investigate the relationship between sarcoplasmic reticulum Ca²⁺ modulation proteins and postresuscitation myocardial dysfunction. Thirty-eight SPF male Sprague-Dawley (SD) rats were randomly divided into control group (n=12) and cardiac arrest (CA) group (n=26). CA was induced by intravenous bolus of potassium chloride (40 μg/g), and cardiopulmonary resuscitation (CPR) was conducted 8 minutes later. No CA was induced in control group except catheter placement for monitoring cardiopulmonary parameters after anesthesia. Invasive hemodynamic parameters were monitored for 1 hour after CPR. Echocardiogram was performed to evaluate cardiac function. Myocardial samples were harvested 5 minutes and 1 hour after restoration of spontaneous circulation (ROSC), and sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a), phosphorylated phospholamban (p-PLB) and rynodine receptor (RyR) were determined by Western Blot. ROSC rate of CA group was 92.3% (24/26), and mean recovery time was (68 ± 39) seconds. Cardiac function was significantly impaired in CA group at 1 hour after resuscitation, and ejection fraction, fraction shortening (FS), the maximal rate of left ventricular pressure increase/decline (± dp/dt max) were significantly decreased compared with those in control group [ejection fraction: 0.548 ± 0.060 vs. 0.809 ± 0.043, F=71.692, P=0.000; FS: (34.4 ± 4.4)% vs. (46.0 ± 3.5)%, F=55.443, P=0.000; + dp/dt max (mmHg/s): 4 718 ± 43 vs. 7 098 ± 394, P<0.01; - dp/dt max (mmHg/s): -3 824 ± 612 vs. -6 187 ± 473, P<0.01]. Compared with control group, the expression levels of p-PLB (gray value) was significantly decreased at 5 minutes and 60 minutes (5 minutes: 0.64 ± 0.15 vs. 1.29 ± 0.13, P<0.01; 60 minutes: 0.95 ± 0.08 vs. 1.30 ± 0.09, P<0.05) after resuscitation in CA group, while the level of sarcoplasmic SERCA2a (gray value) and RyR (gray value) showed no significant differences (SERCA2a 5 minutes: 1.01 ± 0.18 vs. 1.24 ± 0.07, 60 minutes: 1.03 ± 0.14 vs. 1.25 ± 0.06; RyR 5 minutes: 0.96 ± 0.13 vs. 0.97 ± 0.13, 60 minutes: 0.88 ± 0.14 vs. 0.99 ± 0.11, all P>0.05). The impairment of the p-PLB is closely related to postresuscitation myocardial dysfunction.