Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest.

Importance: Blood phosphorylated tau (p-tau) and amyloid-ß peptides (Aß) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. Objective: To evaluate whether the levels and trajectories of blood p-tau, Aß42, and Aß40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest. Design, Setting, and Participants: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aß42, and Aß40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest. Exposures: Serum p-tau, Aß42, and Aß40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators. Main Outcomes and Measures: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). Results: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aß42 and Aß40 concentrations increased over time in most patients but were only weakly associated with neurological outcome. Conclusions and Relevance: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aß peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Brain injury markers in blood predict signs of hypoxic ischaemic encephalopathy on head computed tomography after cardiac arrest.

BACKGROUND/AIM: Signs of hypoxic ischaemic encephalopathy (HIE) on head computed tomography (CT) predicts poor neurological outcome after cardiac arrest. We explore whether levels of brain injury markers in blood could predict the likelihood of HIE on CT. METHODS: Retrospective analysis of CT performed at 24-168 h post cardiac arrest on clinical indication within the Target Temperature Management after out-of-hospital cardiac arrest-trial. Biomarkers prospectively collected at 24- and 48 h post-arrest were analysed for neuron specific enolase (NSE), neurofilament light (NFL), total-tau and glial fibrillary acidic protein (GFAP). HIE was assessed through visual evaluation and quantitative grey-white-matter ratio (GWR) was retrospectively calculated on Swedish subjects with original images available. RESULTS: In total, 95 patients were included. The performance to predict HIE on CT (performed at IQR 73-116 h) at 48 h was similar for all biomarkers, assessed as area under the receiving operating characteristic curve (AUC) NSE 0.82 (0.71-0.94), NFL 0.79 (0.67-0.91), total-tau 0.84 (0.74-0.95), GFAP 0.79 (0.67-0.90). The predictive performance of biomarker levels at 24 h was AUC 0.72-0.81. At 48 h biomarker levels below Youden Index accurately excluded HIE in 77.3-91.7% (negative predictive value) and levels above Youden Index correctly predicted HIE in 73.3-83.7% (positive predictive value). NSE cut-off at 48 h was 48 ng/ml. Elevated biomarker levels irrespective of timepoint significantly correlated with lower GWR. CONCLUSION: Biomarker levels can assess the likelihood of a patient presenting with HIE on CT and could be used to select suitable patients for CT-examination during neurological prognostication in unconscious cardiac arrest patients.

Circular RNAs to predict clinical outcome after cardiac arrest.

BACKGROUND: Cardiac arrest (CA) represents the third leading cause of death worldwide. Among patients resuscitated and admitted to hospital, death and severe neurological sequelae are frequent but difficult to predict. Blood biomarkers offer clinicians the potential to improve prognostication. Previous studies suggest that circulating non-coding RNAs constitute a reservoir of novel biomarkers. Therefore, this study aims to identify circulating circular RNAs (circRNAs) associated with clinical outcome after CA. RESULTS: Whole blood samples obtained 48 h after return of spontaneous circulation in 588 survivors from CA enrolled in the Target Temperature Management trial (TTM) were used in this study. Whole transcriptome RNA sequencing in 2 groups of 23 sex-matched patients identified 28 circRNAs associated with neurological outcome and survival. The circRNA circNFAT5 was selected for further analysis using quantitative PCR. In the TTM-trial (n = 542), circNFAT5 was upregulated in patients with poor outcome as compared to patients with good neurological outcome (p < 0.001). This increase was independent of TTM regimen and sex. The adjusted odds ratio of circNFAT5 to predict neurological outcome was 1.39 [1.07-1.83] (OR [95% confidence interval]). CircNFAT5 predicted 6-month survival with an adjusted hazard ratio of 1.31 [1.13-1.52]. CONCLUSION: We identified circulating circRNAs associated with clinical outcome after CA, among which circNFAT5 may have potential to aid in predicting neurological outcome and survival when used in combination with established biomarkers of CA.

Neurological pupil index and its association with other prognostic tools after cardiac arrest: A post hoc analysis.

INTRODUCTION: We evaluated the concordance of the Neurological pupil Index (NPi) with other predictors of outcome after cardiac arrest (CA). METHODS: Post hoc analysis of a prospective, international, multicenter study including adult CA patients. Predictors of unfavorable outcome (UO, Cerebral Performance Category of 3-5 at 3 months) included: a) worst NPi ≤ 2; b) presence of discontinuous encephalography (EEG) background; c) bilateral absence of N20 waves on somatosensory evoked potentials (N20ABS); d) peak neuron-specific enolase (NSE) blood levels > 60 mcg/L; e) myoclonus, which were all tested in a subset of patients who underwent complete multimodal assessment (MMM). RESULTS: A total of 269/456 (59 %) patients had UO and 186 (41 %) underwent MMM. The presence of myoclonus was assessed in all patients, EEG in 358 (78 %), N20 in 186 (41 %) and NSE measurement in 228 (50 %). Patients with discontinuous EEG, N20ABS or high NSE had a higher proportion of worst NPi ≤ 2. The accuracy for NPi to predict a discontinuous EEG, N20ABS, high NSE and the presence of myoclonus was moderate. Concordance with NPi ≤ 2 was high for NSE, and moderate for discontinuous EEG and N20ABS. Also, the higher the number of concordant predictors of poor outcome, the lower the observed NPi. CONCLUSIONS: In this study, NPi ≤ 2 had moderate to high concordance with other unfavorable outcome prognosticators of hypoxic-ischemic brain injury. This indicates that NPi measurement could be considered as a valid tool for coma prognostication after cardiac arrest.

Impact of Ambient Temperature on 5 Emergency Drugs Aboard an Emergency Medical Car Over a 1-Year Period.

STUDY OBJECTIVE: Drugs in emergency medical service (EMS) cars are often exposed to temperature variations that could affect the stability of these drugs. We aimed to study the influence of real-life temperature exposure on the stability of 5 drugs onboard an EMS vehicle. METHODS: Concentrations of active principles of 5 emergency drugs (amiodarone, rocuronium, fentanyl, succinylcholine, and epinephrine) aboard an EMS vehicle were analyzed every 3 months up to 1 year. The samples were compared to the same drugs stored for 1 year either at room temperature or in a refrigerator in the pharmacy. Succinylcholine was additionally analyzed once a week for 4 weeks after being taken out of the refrigerator. The dosage of the active principle was measured using high-pressure liquid chromatography coupled with ultraviolet detection. RESULTS: After the 12-month period, all drugs from the EMS car, except succinylcholine, presented concentrations still above 90% of the concentrations measured at the start of the project. Concentrations ranged from 96.3% to 103%. For succinylcholine at 12 months, the remaining concentration was 89%. Temperatures in the EMS car ranged from 13.9 °C to 33.9 °C (median, 22.8 °C [interquartile range, 20.5 °C to 25.8 °C]). CONCLUSION: In real-life conditions, amiodarone, rocuronium, fentanyl, succinylcholine, and epinephrine onboard an EMS vehicle did not suffer pharmacologically relevant degradation from temperature variations. All concentrations measured remained in the specification intervals given by the manufacturers.

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest.

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006-2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1-2) versus poor (CPC 3-5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46-0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.

Association Between EEG Patterns and Serum Neurofilament Light After Cardiac Arrest: A Post Hoc Analysis of the TTM Trial.

BACKGROUND AND OBJECTIVES: EEG is widely used for prediction of neurologic outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explored the association between EEG and neurofilament light (NfL) as a marker of neuroaxonal injury, evaluated whether highly malignant EEG patterns are reflected by high NfL levels, and explored the association of EEG backgrounds and EEG discharges with NfL. METHODS: We performed a post hoc analysis of the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours postarrest. Patients who awoke or died prior to 36 hours postarrest were excluded. EEG experts blinded to clinical information classified EEG background, amount of discharges, and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NfL after trial completion. The highest available concentration at 48 or 72 hours postarrest was used. RESULTS: A total of 262/939 patients with EEG and NfL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NfL levels than patients with malignant patterns and NfL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI 1.4-6.1 and 6.5-26.2, respectively; effect size 0.47; p < 0.001). Both background and the amount of discharges were independently strongly associated with NfL levels (p < 0.001). The EEG background had a stronger association with NfL levels than EEG discharges (R2 = 0.30 and R2 = 0.10, respectively). NfL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression, and suppression, respectively: 2.26-18.06, 3.91-41.71, and 5.74-41.74; effect size 0.30; p < 0.001 for all). NfL levels did not differ between suppression and burst suppression. Superimposed discharges were only associated with higher NfL levels if the EEG background was continuous. DISCUSSION: Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NfL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NfL may be useful to better identify patients misclassified by single methods. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT01020916.

Hypothermic versus Normothermic Temperature Control after Cardiac Arrest.

BACKGROUND: The evidence for temperature control for comatose survivors of cardiac arrest is inconclusive. Controversy exists as to whether the effects of hypothermia differ per the circumstances of the cardiac arrest or patient characteristics. METHODS: An individual patient data meta-analysis of the Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest (TTM) and Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trials was conducted. The intervention was hypothermia at 33°C and the comparator was normothermia. The primary outcome was all-cause mortality at 6 months. Secondary outcomes included poor functional outcome (modified Rankin scale score of 4 to 6) at 6 months. Predefined subgroups based on the design variables in the original trials were tested for interaction with the intervention as follows: age (older or younger than the median), sex (female or male), initial cardiac rhythm (shockable or nonshockable), time to return of spontaneous circulation (above or below the median), and circulatory shock on admission (presence or absence). RESULTS: The primary analyses included 2800 patients, with 1403 assigned to hypothermia and 1397 to normothermia. Death occurred for 691 of 1398 participants (49.4%) in the hypothermia group and 666 of 1391 participants (47.9%) in the normothermia group (relative risk with hypothermia, 1.03; 95% confidence interval [CI], 0.96 to 1.11; P=0.41). A poor functional outcome occurred for 733 of 1350 participants (54.3%) in the hypothermia group and 718 of 1330 participants (54.0%) in the normothermia group (relative risk with hypothermia, 1.01; 95% CI, 0.94 to 1.08; P=0.88). Outcomes were consistent in the predefined subgroups. CONCLUSIONS: Hypothermia at 33°C did not decrease 6-month mortality compared with normothermia after out-of-hospital cardiac arrest. (Funded by Vetenskapsrådet; ClinicalTrials.gov numbers NCT02908308 and NCT01020916.)

Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest.

PURPOSE: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered "indeterminate". We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines. METHODS: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1-2) at 6 months. RESULTS: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2-98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87-95% of patients). Normal S100B and NSE predicted good outcome with NPV 76-82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as "indeterminate outcome" by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome. CONCLUSION: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.

Influence of sex on survival, neurologic outcomes, and neurodiagnostic testing after out-of-hospital cardiac arrest.

AIM: Previous studies evaluating the relationship between sex and post-resuscitation care and outcomes following out-of-hospital cardiac arrest (OHCA) are conflicting. We investigated the association between sex and outcomes as well as neurodiagnostic testing in a prospective multicenter international registry of patients admitted to intensive care units following OHCA. METHODS: OHCA survivors enrolled in the International Cardiac Arrest Registry (INTCAR) from 2012 to 2017 were included. We assessed the independent association between sex and survival to hospital discharge, good neurologic outcome (Cerebral Performance Category 1 or 2), neurodiagnostic testing, and withdrawal of life-sustaining therapy (WLST). RESULTS: Of 2407 eligible patients, 809 (33.6%) were women. Baseline characteristics differed by sex, with less bystander CPR and initial shockable rhythms among women. Women were less likely to survive to hospital discharge, however significance abated following adjusted analysis (30.1% vs 42.7%, adjusted OR 0.85, 95% CI 0.67-1.08). Women were less likely to have good neurologic outcome at discharge (21.4% vs 34.0%, adjusted OR 0.74, 95% CI 0.57-0.96) and at six months post-arrest (16.7% vs 29.4%, adjusted OR 0.73, 95% CI 0.54-0.98) that persisted after adjustment. Neuroimaging (75.5% vs 74.3%, p = 0.54) and other neurophysiologic testing (78.8% vs 78.6%, p = 0.91) was similar across sex. Women were more likely to undergo WLST (55.6% vs 42.8%, adjusted OR 1.35, 95% CI 1.09-1.66). CONCLUSIONS: Women with cardiac arrest have lower odds of good neurologic outcomes and higher odds of WLST, despite comparable rates of neurodiagnostic testing and after controlling for baseline differences in clinical characteristics and cardiac arrest features.

Incidence of cardiac interventions and associated cardiac arrest outcomes in patients with nonshockable initial rhythms and no ST elevation post resuscitation.

BACKGROUND: Out of Hospital Cardiac arrest (OHCA) survivors with ST elevation (STE) with or without shockable rhythms often benefit from coronary angiography (CAG) and, if indicated, percutaneous coronary intervention (PCI). However, the benefits of CAG and PCI in OHCA survivors with nonshockable rhythms (PEA/asystole) and no STE are debated. METHODS: Using the International Cardiac Arrest Registry (INTCAR 2.0), representing 44 centers in the US and Europe, comatose OHCA survivors with known presenting rhythms and post resuscitation ECGs were identified. Survival to hospital discharge, neurological recovery on discharge, and impact of CAG with or without PCI on such outcome were assessed and compared with other groups (shockable rhythms with or without STE). RESULTS: Total of 2113 OHCA survivors were identified and described as; nonshockable/no STE (Nsh-NST) (n = 940, 44.5%), shockable/no STE (Sh-NST) (n = 716, 33.9%), nonshockable/STE (Nsh-ST) (n = 110, 5.2%), and shockable/STE (Sh-ST) (n = 347, 16.4%). Of Nsh-NST, 13.7% (129) were previously healthy before CA and only 17.3% (161) underwent CAG; of those, 30.4% (52) underwent PCI. A total of 18.6% (174) Nsh-NST patients survived to hospital discharge, with 57.5% (100) of such survivors having good neurological recovery (cerebral performance category 1 or 2) on discharge. Coronary angiography was associated with improved odds for survival and neurological recovery among all groups, including those with NSh-NST. CONCLUSIONS: Nonshockable initial rhythms with no ST elevation post resuscitation was the most common presentation after OHCA. Although most of these patients did not undergo coronary angiography, among those who did, 1 in 4 patients had a culprit lesion and underwent revascularization. Invasive CAG should be at least considered for all OHCA survivors, including those with nonshockable rhythms and no ST elevation post resuscitation. BRIEF ABSTRACT: Out of hospital cardiac arrest (OHCA) survivors with ST elevation and/or shockable rhythms benefit from coronary angiography and revascularization. Nonshockable cardiac arrest survivors with no ST elevation have the worst prognosis and rarely undergo coronary angiography. Nonshockable rhythms with no ST elevation was the most common presentation after OHCA and among a small subgroup underwent coronary angiography, 1 in 4 patients with had culprit lesion and underwent revascularization. Coronary angiography was associated with high prevalence of acute culprit coronary lesions and should be considered for those with a probably cardiac cause for their arres.

Predicting neurological outcome after out-of-hospital cardiac arrest with cumulative information; development and internal validation of an artificial neural network algorithm.

BACKGROUND: Prognostication of neurological outcome in patients who remain comatose after cardiac arrest resuscitation is complex. Clinical variables, as well as biomarkers of brain injury, cardiac injury, and systemic inflammation, all yield some prognostic value. We hypothesised that cumulative information obtained during the first three days of intensive care could produce a reliable model for predicting neurological outcome following out-of-hospital cardiac arrest (OHCA) using artificial neural network (ANN) with and without biomarkers. METHODS: We performed a post hoc analysis of 932 patients from the Target Temperature Management trial. We focused on comatose patients at 24, 48, and 72 h post-cardiac arrest and excluded patients who were awake or deceased at these time points. 80% of the patients were allocated for model development (training set) and 20% for internal validation (test set). To investigate the prognostic potential of different levels of biomarkers (clinically available and research-grade), patients' background information, and intensive care observation and treatment, we created three models for each time point: (1) clinical variables, (2) adding clinically accessible biomarkers, e.g., neuron-specific enolase (NSE) and (3) adding research-grade biomarkers, e.g., neurofilament light (NFL). Patient outcome was the dichotomised Cerebral Performance Category (CPC) at six months; a good outcome was defined as CPC 1-2 whilst a poor outcome was defined as CPC 3-5. The area under the receiver operating characteristic curve (AUROC) was calculated for all test sets. RESULTS: AUROC remained below 90% when using only clinical variables throughout the first three days in the ICU. Adding clinically accessible biomarkers such as NSE, AUROC increased from 82 to 94% (p < 0.01). The prognostic accuracy remained excellent from day 1 to day 3 with an AUROC at approximately 95% when adding research-grade biomarkers. The models which included NSE after 72 h and NFL on any of the three days had a low risk of false-positive predictions while retaining a low number of false-negative predictions. CONCLUSIONS: In this exploratory study, ANNs provided good to excellent prognostic accuracy in predicting neurological outcome in comatose patients post OHCA. The models which included NSE after 72 h and NFL on all days showed promising prognostic performance.

Risk Stratification Among Survivors of Cardiac Arrest Considered for Coronary Angiography.

BACKGROUND: The American College of Cardiology Interventional Council published consensus-based recommendations to help identify resuscitated cardiac arrest patients with unfavorable clinical features in whom invasive procedures are unlikely to improve survival. OBJECTIVES: This study sought to identify how many unfavorable features are required before prognosis is significantly worsened and which features are most impactful in predicting prognosis. METHODS: Using the INTCAR (International Cardiac Arrest Registry), the impact of each proposed "unfavorable feature" on survival to hospital discharge was individually analyzed. Logistic regression was performed to assess the association of such unfavorable features with poor outcomes. RESULTS: Seven unfavorable features (of 10 total) were captured in 2,508 patients successfully resuscitated after cardiac arrest (ongoing cardiopulmonary resuscitation and noncardiac etiology were exclusion criteria in our registry). Chronic kidney disease was used in lieu of end-stage renal disease. In total, 39% survived to hospital discharge. The odds ratio (OR) of survival to hospital discharge for each unfavorable feature was as follows: age >85 years OR: 0.30 (95% CI: 0.15 to 0.61), time-to-ROSC >30 min OR: 0.30 (95% CI: 0.23 to 0.39), nonshockable rhythm OR: 0.39 (95% CI: 0.29 to 0.54), no bystander cardiopulmonary resuscitation OR: 0.49 (95% CI: 0.38 to 0.64), lactate >7 mmol/l OR: 0.50 (95% CI: 0.40 to 0.63), unwitnessed arrest OR: 0.58 (95% CI: 0.44 to 0.78), pH <7.2 OR: 0.78 (95% CI: 0.63 to 0.98), and chronic kidney disease OR: 0.96 (95% CI: 0.70 to 1.33). The presence of any 3 or more unfavorable features predicted <40% survival. Presence of the 3 strongest risk factors (age >85 years, time-to-ROSC >30 min, and non-ventricular tachycardia/ventricular fibrillation) together or ≥6 unfavorable features predicted a ≤10% chance of survival to discharge. CONCLUSIONS: Patients successfully resuscitated from cardiac arrest with 6 or more unfavorable features have a poor long-term prognosis. Delaying or even forgoing invasive procedures in such patients is reasonable.

The association of partial pressures of oxygen and carbon dioxide with neurological outcome after out-of-hospital cardiac arrest: an explorative International Cardiac Arrest Registry 2.0 study.

BACKGROUND: Exposure to extreme arterial partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2) following the return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) is common and may affect neurological outcome but results of previous studies are conflicting. METHODS: Exploratory study of the International Cardiac Arrest Registry (INTCAR) 2.0 database, including 2162 OHCA patients with ROSC in 22 intensive care units in North America and Europe. We tested the hypothesis that exposure to extreme PaO2 or PaCO2 values within 24 h after OHCA is associated with poor neurological outcome at discharge. Our primary analyses investigated the association between extreme PaO2 and PaCO2 values, defined as hyperoxemia (PaO2 > 40 kPa), hypoxemia (PaO2 < 8.0 kPa), hypercapnemia (PaCO2 > 6.7 kPa) and hypocapnemia (PaCO2 < 4.0 kPa) and neurological outcome. The secondary analyses tested the association between the exposure combinations of PaO2 > 40 kPa with PaCO2 < 4.0 kPa and PaO2 8.0-40 kPa with PaCO2 > 6.7 kPa and neurological outcome. To define a cut point for the onset of poor neurological outcome, we tested a model with increasing and decreasing PaO2 levels and decreasing PaCO2 levels. Cerebral Performance Category (CPC), dichotomized to good (CPC 1-2) and poor (CPC 3-5) was used as outcome measure. RESULTS: Of 2135 patients eligible for analysis, 700 were exposed to hyperoxemia or hypoxemia and 1128 to hypercapnemia or hypocapnemia. Our primary analyses did not reveal significant associations between exposure to extreme PaO2 or PaCO2 values and neurological outcome (P = 0.13-0.49). Our secondary analyses showed no significant associations between combinations of PaO2 and PaCO2 and neurological outcome (P = 0.11-0.86). There was no PaO2 or PaCO2 level significantly associated with poor neurological outcome. All analyses were adjusted for relevant co-variates. CONCLUSIONS: Exposure to extreme PaO2 or PaCO2 values in the first 24 h after OHCA was common, but not independently associated with neurological outcome at discharge.

Performance of a guideline-recommended algorithm for prognostication of poor neurological outcome after cardiac arrest.

PURPOSE: To assess the performance of a 4-step algorithm for neurological prognostication after cardiac arrest recommended by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). METHODS: Retrospective descriptive analysis with data from the Target Temperature Management (TTM) Trial. Associations between predicted and actual neurological outcome were investigated for each step of the algorithm with results from clinical neurological examinations, neuroradiology (CT or MRI), neurophysiology (EEG and SSEP) and serum neuron-specific enolase. Patients examined with Glasgow Coma Scale Motor Score (GCS-M) on day 4 (72-96 h) post-arrest and available 6-month outcome were included. Poor outcome was defined as Cerebral Performance Category 3-5. Variations of the ERC/ESICM algorithm were explored within the same cohort. RESULTS: The ERC/ESICM algorithm identified poor outcome patients with 38.7% sensitivity (95% CI 33.1-44.7) and 100% specificity (95% CI 98.8-100) in a cohort of 585 patients. An alternative cut-off for serum neuron-specific enolase, an alternative EEG-classification and variations of the GCS-M had minor effects on the sensitivity without causing false positive predictions. The highest overall sensitivity, 42.5% (95% CI 36.7-48.5), was achieved when prognosticating patients irrespective of GCS-M score, with 100% specificity (95% CI 98.8-100) remaining. CONCLUSION: The ERC/ESICM algorithm and all exploratory multimodal variations thereof investigated in this study predicted poor outcome without false positive predictions and with sensitivities 34.6-42.5%. Our results should be validated prospectively, preferably in patients where withdrawal of life-sustaining therapy is uncommon to exclude any confounding from self-fulfilling prophecies.

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 GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients.

OBJECTIVE: Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest. METHODS: Serum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE. RESULTS: 717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88-0.89; UCH-L1 0.85-0.87) or in combination (AUROC 0.90-0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75-0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h. CONCLUSION: GFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE.

Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial.

BACKGROUND: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest. METHODS: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score. RESULTS: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001. CONCLUSION: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure. TRIAL REGISTRATION: Clinical Trials, NCT01020916. Registered November 26, 2009.

Functional outcomes associated with varying levels of targeted temperature management after out-of-hospital cardiac arrest - An INTCAR2 registry analysis.

INTRODUCTION: Targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) has been recommended in international guidelines since 2005. The TTM-trial published in 2013 showed no difference in survival or neurological outcome for patients randomised to 33 °C or 36 °C, and many hospitals have changed practice. The optimal utilization of TTM is still debated. This study aimed to analyse if a difference in temperature goal was associated with outcome in an unselected international registry population. METHODS: This is a retrospective observational study based on a prospective registry - the International Cardiac Arrest Registry 2. Patients were categorized as receiving TTM in the lower range at 32-34 °C (TTM-low) or at 35-37 °C (TTM-high). Primary outcome was good functional status defined as cerebral performance category (CPC) of 1-2 at hospital discharge and secondary outcome was adverse events related to TTM. A logistic regression model was created to evaluate the independent effect of temperature by correcting for clinical and demographic factors associated with outcome. RESULTS: Of 1710 patients included, 1242 (72,6%) received TTM-low and 468 (27,4%) TTM-high. In patients receiving TTM-low, 31.3% survived with good outcome compared to 28.8% in the TTM-high group. There was no significant association between temperature and outcome (p = 0.352). In analyses adjusted for baseline differences the OR for a good outcome with TTM-low was 1.27, 95% CI (0.94-1.73). Haemodynamic instability leading to discontinuation of TTM was more common in TTM-low. CONCLUSIONS: No significant difference in functional outcome at hospital discharge was found in patients receiving lower- versus higher targeted temperature management.