The Role of Chest Compressions on Ventilation during Advanced Cardiopulmonary Resuscitation.

Background: There is growing interest in the quality of manual ventilation during cardiopulmonary resuscitation (CPR), but accurate assessment of ventilation parameters remains a challenge. Waveform capnography is currently the reference for monitoring ventilation rate in intubated patients, but fails to provide information on tidal volumes and inspiration-expiration timing. Moreover, the capnogram is often distorted when chest compressions (CCs) are performed during ventilation compromising its reliability during CPR. Our main purpose was to characterize manual ventilation during CPR and to assess how CCs may impact on ventilation quality. Methods: Retrospective analysis were performed of CPR recordings fromtwo databases of adult patients in cardiac arrest including capnogram, compression depth, and airway flow, pressure and volume signals. Using automated signal processing techniques followed by manual revision, individual ventilations were identified and ventilation parameters were measured. Oscillations on the capnogram plateau during CCs were characterized, and its correlation with compression depth and airway volume was assessed. Finally, we identified events of reversed airflow caused by CCs and their effect on volume and capnogram waveform. Results: Ventilation rates were higher than the recommended 10 breaths/min in 66.7% of the cases. Variability in ventilation rates correlated with the variability in tidal volumes and other ventilatory parameters. Oscillations caused by CCs on capnograms were of high amplitude (median above 74%) and were associated with low pseudo-volumes (median 26 mL). Correlation between the amplitude of those oscillations with either the CCs depth or the generated passive volumes was low, with correlation coefficients of -0.24 and 0.40, respectively. During inspiration and expiration, reversed airflow events caused opposed movement of gases in 80% of ventilations. Conclusions: Our study confirmed lack of adherence between measured ventilation rates and the guideline recommendations, and a substantial dispersion in manual ventilation parameters during CPR. Oscillations on the capnogram plateau caused by CCs did not correlate with compression depth or associated small tidal volumes. CCs caused reversed flow during inspiration, expiration and in the interval between ventilations, sufficient to generate volume changes and causing oscillations on capnogram. Further research is warranted to assess the impact of these findings on ventilation quality during CPR.

Prehospital emergency medicine research by additional teams on scene - Concepts and lessons learned.

While the initial minutes of acute emergencies significantly influence clinical outcomes, prehospital research often receives inadequate attention due to several challenges. Retrospective chart reviews carry the risk of incomplete and inaccurate data. Furthermore, prehospital intervention trials frequently encounter difficulties related to extensive training requirements, even during the planning phase. Consequently, we have implemented prospective research concepts involving additional paramedics and physicians directly at the scene during major emergency calls. Three concepts were used: (I) Paramedic field supervisor units, (II) a paramedic + physician field supervisor unit, (III) a special physician-based research car. This paper provides insights into our historical perspective, the current situation, and the lessons learned while overcoming certain barriers and using existing and novel facilitators. Our objective is to support other research groups with our experiences in their planning of upcoming prehospital trials.

Exploring the Synergy of Music and Medicine in Healthcare: Expert Insights into the Curative and Societal Role of the Relationship between Music and Medicine.

Our study aimed to investigate the correlation between medicine, health perception, and music as well as the role of music in the healthcare setting. To gain insights into the dynamics between these two fields, we gathered opinions from attendees and presenters at an international conference on music medicine, musicians' health, and music therapy. A team of six interviewers conducted a total of 26 semi-structured interviews. The interview guide focused on four predetermined themes: (1) "music in medicine", (2) "performing arts medicine", (3) "music for the individual", and (4) "music for society". The responses were analyzed using grounded theory methods as well as thematic and content analysis. To enhance the analytical strength, investigator triangulation was employed. Within the predefined themes, we identified several subthemes. Theme 1 encompassed topics such as "listening and performing music for treating diseases and establishing non-verbal relationships", "the value of music in specific disorders, end-of-life care, and pain management", and "the design of sound spaces". Theme 2 explored aspects including the "denial and taboo surrounding physical and mental health issues among musicians", "the importance of prevention", and an antithesis: "pain and suffering driving creativity". Theme 3 addressed the "mental role of music in ordinary and extraordinary life" as well as "music's ability to enable self-conditioning". Lastly, Theme 4 examined the role of music in "cultural self-identification" and "development and education for children". Throughout the interviews, participants expressed a lack of knowledge and awareness regarding interdisciplinary research and the fields of music and medicine. Our findings affirm the significance of music therapy and performing arts medicine as well as the broader relationship between music and medicine. They highlight the potential benefits of perception and experiential pathways for individuals and, consequently, for human society.

A six-year teaching life supportive first aid program to eventually generate peer trainer pupils: a prospective case control study.

BACKGROUND: Out of hospital cardiac arrest is a life-threatening condition. To improve the chances of survival, lay-person cardio-pulmonary-resuscitation (CPR) is a crucial factor. Many bystanders fail to react appropriately, even if life supporting first aid (LSFA) programs and campaigns including CPR tried to increase the handling of basic cardiac life support. To achieve an enhanced learning of CPR a pupil's grade after grade teaching program was established in a school with medical students. METHODS: The learning of CPR was investigated in a prospective, case-controlled study at an international school. Pupils (12 ± 3 years old) joining our LSFA courses (n = 538, female: 243, attendance for evaluation: 476) were compared to a control group (n = 129, female: 52, attendance for evaluation: 102). Surveys and quality of CPR (QCPR%) through a computer linked "Resusci Anne" dummy were compared with Chi-squared tests, t-tests pair wisely, and by one-way ANOVA. RESULTS: Knowledge and skills on the "Resusci Anne" were significantly better in trained grade 9 pupils compared to the control group (QCPR, 59 vs. 25%). The number of LSFA courses each grade 9 student had, correlated with improved practical performance (r2 = 0.21, p < 0.001). The willingness to deliver CPR to strangers increased with improved practical performance. Attitudes towards performing CPR were high in all participating grades. CONCLUSION: Repetitive teaching LSFA to grade 5-9 pupil's grade after grade by medical students has been successfully established. Pupils who finish the program will eventually be able to teach LSFA to younger students. This is furthermore a good way of sharing a "learning by teaching" role and it enables to have more pupils as trainers who can provide instruction to a larger number of pupils with the purpose of having a better-trained population in LSFA.

Lapses of the Heart: Frequency and Subjective Salience of Impressions Reported by Patients after Cardiac Arrest.

After cardiac arrest (CA), some patients report impressions with highly realistic features, often referred to as near-death experience (NDE). The frequency of such episodes seems to be variable, with various types of content. In a prospective study, we subjected 126 CA cases treated at the Department of Emergency Medicine of the Medical University of Vienna under carefully controlled conditions to a structured interview. We included all patients admitted due to CA, whose communicative abilities were restored and who agreed to participate in the study. The questionnaire inquired as to living conditions, attitudes towards issues of life and death, and last recollections before and first impressions after the CA. The majority of the subjects (91 = 76%) replied to inquiries concerning impressions during CA with "nothing" or "blackout", but 20 (16%) gave a detailed account. A German version of the Greyson questionnaire specifically addressing NDE phenomena (included towards the end of the interview) resulted in ≥7 points in five patients (4%). Three patients reported a meeting with deceased relatives (one with 6 Greyson points), one an out-of-body episode, and one having been sucked into a colorful tunnel. Eleven of these twenty cases had their cardiopulmonary resuscitation (CPR) started within the first min of CA, a higher fraction than cases without experience. Reported experience after CA was of high significance for the patients; many of them changed their point of view on issues of life and death.

Very long-term survivors of in-hospital and out-of-hospital cardiac arrest show considerable impairment of daily life.

BACKGROUND: Reliable data on long-term outcomes after cardiac arrest (CA) remain scarce. Identifying factors persistently impacting the quality of life after CA is crucial to improve long-term outcomes. METHODS: Adult in- and out-of-hospital CA patients surviving to hospital discharge between 1996 and 2015 were retrospectively included. We classified survivors in stages of survival time and assessed long-term survival and quality of life by contacting patients via a standardized telephone questionnaire including the modified Rankin Scale (mRS). RESULTS: Of 4,234 patients, 1,573 (37.2%) survived to hospital discharge. Among those, 693(44.1%) were alive at the time of the interview. We obtained interviews in 178 patients at a survival time of 7.8 (4.2-12.6) years. Younger age, female gender, and shorter duration of initial hospitalization and coma were associated with long-term survival. Conversely, higher median age at time of CA predicted poor outcome (mRS ≥ 3) and impaired quality of daily life. Around 25% declared being impaired in mobility, with female gender and higher age being predictors. Impairment in personal care and hygiene was stated in 11.8%, and activities of daily life such as shopping troubled 33.1%. Chronic pain impairing daily life was reported in 47.2% of cases, and lower socioeconomic status was suggestive of unfavourable outcome. CONCLUSION: Very long-term survivors showed considerable impairment of quality of life in terms of reduced mobility, self-care, or chronic pain. Higher age at time of CA and lower socioeconomic status showed worse outcomes. A more personalized screening of survivors for risk factors and long-term support are suggested.

Prediction of Neurological Recovery After Cardiac Arrest Using Neurofilament Light Chain is Improved by a Proteomics-Based Multimarker Panel.

BACKGROUND: Continuous advances in resuscitation care have increased survival, but the rate of favorable neurological outcome remains low. We have shown the usefulness of proteomics in identifying novel biomarkers to predict neurological outcome. Neurofilament light chain (NfL), a marker of axonal damage, has since emerged as a promising single marker. The aim of this study was to assess the predictive value of NfL in comparison with and in addition to our established model. METHODS: NfL was measured in plasma samples drawn at 48 h after cardiac arrest using single-molecule assays. Neurological function was recorded on the cerebral performance category (CPC) scale at discharge from the intensive care unit and after 6 months. The ability to predict a dichotomized outcome (CPC 1-2 vs. 3-5) was assessed with receiver operating characteristic (ROC) curves. RESULTS: Seventy patients were included in this analysis, of whom 21 (30%) showed a favorable outcome (CPC 1-2), compared with 49 (70%) with an unfavorable outcome (CPC 3-5) at discharge. NfL increased from CPC 1 to 5 (16.5 pg/ml to 641 pg/ml, p < 0.001). The addition of NfL to the existing model improved it significantly (Wald test, p < 0.001), and the combination of NfL with a multimarker model showed high areas under the ROC curve (89.7% [95% confidence interval 81.7-97.7] at discharge and 93.7% [88.2-99.2] at 6 months) that were significantly greater than each model alone. CONCLUSIONS: The combination of NfL with other plasma and clinical markers is superior to that of either model alone and achieves high areas under the ROC curve in this relatively small sample.

The association of early diarrhea after successful resuscitation following out-of-hospital cardiac arrest with neurological outcome: A retrospective observational study.

ABSTRACT: Gastrointestinal ischemia with reperfusion tissue injury contributes to post-cardiac arrest syndrome. We hypothesized that diarrhea is a symptom of intestinal ischemia/reperfusion injury and investigated whether the occurrence of early diarrhea (≤12 hours) after successful cardiopulmonary resuscitation is associated with an unfavorable neurological outcome.We analyzed data from the Vienna Clinical Cardiac Arrest Registry. Inclusion criteria comprised ≥18 years of age, a witnessed, non-traumatic out-of-hospital cardiac arrest, return of spontaneous circulation (ROSC), initial shockable rhythm, and ST-segment elevation in electrocardiogram after ROSC with consecutive coronary angiography. Patients with diarrhea caused by other factors (e.g., infections, antibiotic treatment, or chronic diseases) were excluded. The primary endpoint was neurological function between patients with or without "early diarrhea" (≤12 hours after ROSC) according to cerebral performance categories.We included 156 patients between 2005 and 2012. The rate of unfavorable neurologic outcome was higher in patients with early diarrhea (67% vs 37%). In univariate analysis, the crude odds ratio for unfavorable neurologic outcome was 3.42 (95% confidence interval, 1.11-10.56, P = .03) for early diarrhea. After multivariate adjustment for traditional prognostication markers the odds ratio of early diarrhea was 5.90 (95% confidence interval, 1.28-27.06, P = .02).In conclusion, early diarrhea within 12 hours after successful cardiopulmonary resuscitation was associated with an unfavorable neurological outcome.

Copeptin Levels Are Independent from Mild Therapeutic Hypothermia but Do Not Predict Infarct Size in Patients Presenting with ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Mild therapeutic hypothermia (MTH) is a treatment adjunct in ST-segment elevation myocardial infarction (STEMI) that deserves investigation. Copeptin-a surrogate marker for vasopressin-is an early biomarker in STEMI. Data from cardiac arrest patients suggest a reduction of copeptin levels through MTH; however, copeptin levels have not been investigated in MTH during STEMI. METHODS: We analyzed patients treated with MTH during STEMI in a sub-study of the STATIM trial (Testori, Heart 2019). Patients were randomized to normothermia or MTH with out-of-hospital initiation. Seven copeptin samples were collected from each patient. Primary endpoint was the difference in copeptin levels between the groups. As secondary endpoints, we defined differences in the kinetics between the sampling timepoints and the correlation between copeptin and the infarct size in relation to left ventricular myocardium. RESULTS: We included 99 patients (MTH n = 47, control n = 52) in our intention to treat analysis. No differences in copeptin values at first medical contact between the MTH and normothermia groups were found. MTH showed no effect on copeptin levels, neither during cooling phase nor through the course. Copeptin peaked at first medical contact and hospital admission in both groups. No differences in kinetics between the timepoints were found. Copeptin showed no correlation with infarct size, neither at first medical contact nor hospital admission. CONCLUSIONS: Copeptin levels were not influenced by MTH in STEMI, suggesting the use of this biomarker also during temperature management. Furthermore, copeptin levels were not usable as a surrogate marker for infarct size at any timepoint.

Initial Blood pH, Lactate and Base Deficit Add No Value to Peri-Arrest Factors in Prognostication of Neurological Outcome After Out-of-Hospital Cardiac Arrest.

Background: In cardiac arrest survivors, metabolic parameters [pH value, lactate concentration, and base deficit (BD)] are routinely added to peri-arrest factors (including age, sex, bystander cardiopulmonary resuscitation, shockable first rhythm, resuscitation duration, adrenaline dose) to enhance early outcome prediction. However, the additional value of this strategy remains unclear. Methods: We used our resuscitation database to screen all patients ≥18 years who had suffered in- or out-of-hospital cardiac arrest (IHCA, OHCA) between January 1st, 2005 and May 1st, 2019. Patients with incomplete data, without return of spontaneous circulation or treatment with sodium bicarbonate were excluded. To analyse the added value of metabolic parameters to prognosticate neurological function, we built three models using logistic regression. These models included: (1) Peri-arrest factors only, (2) peri-arrest factors plus metabolic parameters and (3) metabolic parameters only. Receiver operating characteristics curves regarding 30-day good neurological function (Cerebral Performance Category 1-2) were analysed. Results: A total of 2,317 patients (OHCA: n = 1842) were included. In patients with OHCA, model 1 and 2 had comparable predictive value. Model 3 was inferior compared to model 1. In IHCA patients, model 2 performed best, whereas both metabolic (model 3) and peri-arrest factors (model 1) demonstrated similar power. PH, lactate and BD had interchangeable areas under the curve in both IHCA and OHCA. Conclusion: Although metabolic parameters may play a role in IHCA, no additional value in the prediction of good neurological outcome could be found in patients with OHCA. This highlights the importance of accurate anamnesis especially in patients with OHCA.

Catalase Predicts In-Hospital Mortality after Out-of-Hospital Cardiac Arrest.

The generation of harmful reactive oxygen species (ROS), including hydrogen peroxide, in out-of-hospital cardiac arrest (OHCA) survivors causes systemic ischemia/reperfusion injury that may lead to multiple organ dysfunction and mortality. We hypothesized that the antioxidant enzyme catalase may attenuate these pathophysiological processes after cardiac arrest. Therefore, we aimed to analyze the predictive value of catalase levels for mortality in OHCA survivors. In a prospective, single-center study, catalase levels were determined in OHCA survivors 48 h after the return of spontaneous circulation. Thirty-day mortality was defined as the study end point. A total of 96 OHCA survivors were enrolled, of whom 26% (n = 25) died within the first 30 days after OHCA. The median plasma intensity levels (log2) of catalase were 8.25 (IQR 7.64-8.81). Plasma levels of catalase were found to be associated with mortality, with an adjusted HR of 2.13 (95% CI 1.07-4.23, p = 0.032). A Kaplan-Meier analysis showed a significant increase in 30-day mortality in patients with high catalase plasma levels compared to patients with low catalase levels (p = 0.012). High plasma levels of catalase are a strong and independent predictor for 30-day mortality in OHCA survivors. This indicates that ROS-dependent tissue damage is playing a crucial role in fatal outcomes of post-cardiac syndrome patients.

Mild Therapeutic Hypothermia Alters Hemostasis in ST Elevation Myocardial Infarction Patients.

Background and Rationale: Mild therapeutic hypothermia (MTH) is a concept to reduce infarct size and improve outcome after ST-segment elevation myocardial infarction (STEMI). In the STATIM trial, we investigated MTH as an additional therapy for STEMI patients. In the intention-to-treat set, 101 patients were included. No difference in primary and secondary endpoints measured by cardiac magnetic resonance imaging was found. Platelet activation and plasmatic coagulation are key in the pathophysiology of STEMI. In the present study, we investigated the effect of MTH on primary and secondary hemostasis in STEMI patients. Methods and Results: Platelet function and morphology were assessed by routine blood count, aggregometry testing, and flow cytometry. Soluble platelet markers were determined by enzyme-linked immunosorbent assay (ELISA) testing. Plasmatic coagulation was measured throughout the study. Platelet count remained unchanged, irrespective of treatment, whereas platelet size decreased in both patient groups. Platelet aggregometry indicated increased platelet reactivity in the MTH group. Furthermore, higher adenosine diphosphate (ADP) plasma levels were found in MTH patients. Expression of glycoprotein IIb/IIIa was increased on platelets of STEMI patients treated with MTH. Lower patient temperatures correlated with longer clotting times and resulted in reduced pH. Lower pH values were positively correlated with longer clotting times. Conclusion: Present data indicate longer clotting times and higher platelet reactivity in STEMI patients treated with MTH. These changes did not correspond to clinical bleeding events or larger infarct size.

Change of Hemoglobin Levels in the Early Post-cardiac Arrest Phase Is Associated With Outcome.

Background: The post-cardiac arrest (CA) phase is characterized by high fluid requirements, endothelial activation and increased vascular permeability. Erythrocytes are large cells and may not leave circulation despite massive capillary leak. We hypothesized that dynamic changes in hemoglobin concentrations may reflect the degree of vascular permeability and may be associated with neurologic function after CA. Methods: We included patients ≥18 years, who suffered a non-traumatic CA between 2013 and 2018 from the prospective Vienna Clinical Cardiac Arrest Registry. Patients without return of spontaneous circulation (ROSC), with extracorporeal life support, with any form of bleeding, undergoing surgery, receiving transfusions, without targeted temperature management or with incomplete datasets for multivariable analysis were excluded. The primary outcome was neurologic function at day 30 assessed by the Cerebral Performance Category scale. Differences of hemoglobin concentrations at admission and 12 h after ROSC were calculated and associations with neurologic function were investigated by uni- and multivariable logistic regression. Results: Two hundred and seventy-five patients were eligible for analysis of which 143 (52%) had poor neurologic function. For every g/dl increase in hemoglobin from admission to 12 h the odds of poor neurologic function increased by 26% (crude OR 1.26, 1.07-1.49, p = 0.006). The effect remained unchanged after adjustment for fluid balance and traditional prognostication markers (adjusted OR 1.27, 1.05-1.54, p = 0.014). Conclusion: Increasing hemoglobin levels in spite of a positive fluid balance may serve as a surrogate parameter of vascular permeability and are associated with poor neurologic function in the early post-cardiac arrest period.

Admission C-reactive protein concentrations are associated with unfavourable neurological outcome after out-of-hospital cardiac arrest.

Whether admission C-reactive protein (aCRP) concentrations are associated with neurological outcome after out-of-hospital cardiac arrest (OHCA) is controversial. Based on established kinetics of CRP, we hypothesized that aCRP may reflect the pre-arrest state of health and investigated associations with neurological outcome. Prospectively collected data from the Vienna Clinical Cardiac Arrest Registry of the Department of Emergency Medicine were analysed. Adults (≥ 18 years) who suffered a non-traumatic OHCA between January 2013 and December 2018, without return of spontaneous circulation or extracorporeal cardiopulmonary resuscitation therapy were eligible. The primary endpoint was a composite of unfavourable neurologic function or death (defined as Cerebral Performance Category 3-5) at 30 days. Associations of CRP levels drawn within 30 min of hospital admission were assessed using binary logistic regression. ACRP concentrations were overall low in our population (n = 832), but higher in the unfavourable outcome group [median: 0.44 (quartiles 0.15-1.44) mg/dL vs. 0.26 (0.11-0.62) mg/dL, p < 0.001]. The crude odds ratio for higher aCRP concentrations was 1.19 (95% CI 1.10-1.28, p < 0.001, per mg/dL) to have unfavourable neurological outcome. After multivariate adjustment for traditional prognostication markers the odds ratio of higher aCRP concentrations was 1.13 (95% CI 1.04-1.22, p = 0.002). Sensitivity of aCRP was low, but specificity for unfavourable neurological outcome was 90% for the cut-off at 1.5 mg/dL and 97.5% for 5 mg/dL CRP. In conclusion, high aCRP levels are associated with unfavourable neurological outcome at day 30 after OHCA.

Gastric regurgitation predicts neurological outcome in out-of-hospital cardiac arrest survivors.

Hypoxic-ischemic brain injury can affect and disturb the autonomous nervous system (ANS), which regulates various visceral systems including the gastro-intestinal and emetic system. The present study aimed to analyze the predictive value of gastric regurgitation (GReg) for neurological outcome in out-of-hospital cardiac arrest (OHCA) survivors. In this prospective, single-center study, 79 OHCA survivors treated at a university-affiliated tertiary care centre were included and GReg was measured at the first day after successful cardiopulmonary resuscitation. Neurological outcome was assessed by the Cerebral Performance Categories score at discharge. Seventy-six percent of the study population had a poor neurological outcome. GReg was found to be associated with poor neurological outcome with an adjusted OR of 5.37 (95% CI 1.41-20.46; p = 0.01). The area under the ROC curve for GReg was 0.69 (95% CI, 0.56-0.81) for poor neurological outcome. GReg on the first day after OHCA is an early, strong and independent predictor for poor neurological outcome in comatose OHCA survivors. These results are particularly compelling because measurement of GReg is inexpensive and routinely performed in critical care units.

Prolonged Activated Partial Thromboplastin Time after Successful Resuscitation from Cardiac Arrest is Associated with Unfavorable Neurologic Outcome.

Coagulation abnormalities after successful resuscitation from cardiac arrest may be associated with unfavorable neurologic outcome. We investigated a potential association of activated partial thromboplastin time (aPTT) with neurologic outcome in adult cardiac arrest survivors. Therefore, we included all adults ≥18 years of age who suffered a nontraumatic cardiac arrest and had achieved return of spontaneous circulation between January 2013 and December 2018. Patients receiving anticoagulants or thrombolytic therapy and those subjected to extracorporeal membrane oxygenation support were excluded. Routine blood sampling was performed on admission as soon as a vascular access was available. The primary outcome was 30-day neurologic function, assessed by the Cerebral Performance Category scale (3-5 = unfavorable neurologic function). Multivariable regression was used to assess associations between normal (≤41 seconds) and prolonged (>41 seconds) aPTT on admission (exposure) and the primary outcome. Results are given as odds ratio (OR) with 95% confidence intervals (95% CIs). Out of 1,591 cardiac arrest patients treated between 2013 and 2018, 360 patients (32% female; median age: 60 years [interquartile range: 48-70]) were eligible for analysis. A total of 263 patients (73%) had unfavorable neurologic function at day 30. aPTT prolongation >41 seconds was associated with a 190% increase in crude OR of unfavorable neurologic function (crude OR: 2.89; 95% CI: 1.78-4.68, p < 0.001) and with more than double the odds after adjustment for traditional risk factors (adjusted OR: 2.01; 95% CI: 1.13-3.60, p = 0.018). In conclusion, aPTT prolongation on admission is associated with unfavorable neurologic outcome after successful resuscitation from cardiac arrest.

Motor Cortex and Hippocampus Display Decreased Heme Oxygenase Activity 2 Weeks After Ventricular Fibrillation Cardiac Arrest in Rats.

Heme oxygenase (HO) and biliverdin reductase (BVR) activities are important for neuronal function and redox homeostasis. Resuscitation from cardiac arrest (CA) frequently results in neuronal injury and delayed neurodegeneration that typically affect vulnerable brain regions, primarily hippocampus (Hc) and motor cortex (mC), but occasionally also striatum and cerebellum. We questioned whether these delayed effects are associated with changes of the HO/BVR system. We therefore analyzed the activities of HO and BVR in the brain regions Hc, mC, striatum and cerebellum of rats subjected to ventricular fibrillation CA (6 min or 8 min) after 2 weeks following resuscitation, or sham operation. From all investigated regions, only Hc and mC showed significantly decreased HO activities, while BVR activity was not affected. In order to find an explanation for the changed HO activity, we analyzed protein abundance and mRNA expression levels of HO-1, the inducible, and HO-2, the constitutively expressed isoform, in the affected regions. In both regions we found a tendency for a decreased immunoreactivity of HO-2 using immunoblots and immunohistochemistry. Additionally, we investigated the histological appearance and the expression of markers indicative for activation of microglia [tumor necrosis factor receptor type I (TNFR1) mRNA and immunoreactivity for ionized calcium-binding adapter molecule 1 (Iba1])], and activation of astrocytes [immunoreactivity for glial fibrillary acidic protein (GFAP)] in Hc and mC. Morphological changes were detected only in Hc displaying loss of neurons in the cornu ammonis 1 (CA1) region, which was most pronounced in the 8 min CA group. In this region also markers indicating inflammation and activation of pro-death pathways (expression of HO-1 and TNFR1 mRNA, as well as Iba1 and GFAP immunoreactivity) were upregulated. Since HO products are relevant for maintaining neuronal function, our data suggest that neurodegenerative processes following CA may be associated with a decreased capacity to convert heme into HO products in particularly vulnerable brain regions.

Proteomics-Enriched Prediction Model for Poor Neurologic Outcome in Cardiac Arrest Survivors.

OBJECTIVES: Neurologic outcome prediction in out-of-hospital cardiac arrest survivors is highly limited due to the lack of consistent predictors of clinically relevant brain damage. The present study aimed to identify novel biomarkers of neurologic recovery to improve early prediction of neurologic outcome. DESIGN: Prospective, single-center study, SETTING:: University-affiliated tertiary care center. PATIENTS: We prospectively enrolled 96 out-of-hospital cardiac arrest survivors into our study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neurologic outcome was assessed by the Cerebral Performance Categories score. To identify plasma biomarkers for poor neurologic outcome (Cerebral Performance Categories score ≥ 3), we performed a three-step proteomics strategy of preselection by shotgun analyses, crosschecking in brain tissue samples, and verification by targeted proteomic analyses using a multistep statistical modeling approach. Sixty-three patients (66%) had a poor neurologic outcome. Out of a total of 299 proteins, we identified α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein as novel biomarkers for poor neurologic outcome. The implementation of these biomarkers into a clinical multimarker model, consisting of previously identified covariates associated to outcome, resulted in a significant improvement of neurologic outcome prediction (C-index, 0.70; explained variation, 11.9%; p for added value, 0.019). CONCLUSIONS: This study identified four novel biomarkers for the prediction of poor neurologic outcome in out-of-hospital cardiac arrest survivors. The implementation of α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein into a multimarker predictive model along with previously identified risk factors significantly improved neurologic outcome prediction. Each of the proteomically identified biomarkers did not only outperform current risk stratification models but may also reflect important pathophysiologic pathways undergoing during cerebral ischemia.