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Background: Head computed tomography (CT) is a guideline recommended method to predict functional outcome after cardiac arrest (CA), but standardized criteria for evaluation are lacking. To date, no prospective trial has systematically validated methods for diagnosing hypoxic-ischaemic encephalopathy (HIE) on CT after CA. We present a protocol for validation of pre-specified radiological criteria for assessment of HIE on CT for neuroprognostication after CA. Methods/design: This is a prospective observational international multicentre substudy of the Targeted Hypothermia versus Targeted Normother-mia after out-of-hospital cardiac arrest (TTM2) trial. Patients still unconscious 48 hours post-arrest at 13 participating hospitals were routinely exam-ined with CT. Original images will be evaluated by examiners blinded to clinical data using a standardized protocol. Qualitative assessment will include evaluation of absence/presence of "severe HIE". Radiodensities will be quantified in pre-specified regions of interest for calculation of grey-white matter ratios (GWR) at the basal ganglia level. Functional outcome will be dichotomized into good (modified Rankin Scale 0-3) and poor (modified Rankin Scale 4-6) at six months post-arrest. Prognostic accuracies for good and poor outcome will be presented as sensitivities and speci-ficities with 95% confidence intervals (using pre-specified cut-offs for quantitative analysis), descriptive statistics (Area Under the Receiver Operating Characteristics Curve), inter-and intra-rater reliabilities according to STARD guidelines. Conclusions: The results from this prospective trial will validate a standardized approach to radiological evaluations of HIE on CT for prediction of functional outcome in comatose CA patients. The TTM2 trial and the TTM2 CT substudy are registered at ClinicalTrials.gov NCT02908308 and NCT03913065.

Out‐of‐hospital cardiac arrest remains a leading cause of mortality in the United States, and the majority of patients who die after achieving return of spontaneous circulation die from withdrawal of care due to a perceived poor neurologic prognosis. Unfortunately, withdrawal of care often occurs during the first day of admission and research suggests this early withdrawal of care may be premature and result in unnecessary deaths for patients who would have made a full neurologic recovery. In this review, we explore the evidence for neurologic prognostication in the emergency department for patients who achieve return of spontaneous circulation after an out‐of‐hospital cardiac arrest.

Cardiac arrest (CA) afflicts ~ 550,000 people each year in the USA. A small fraction of CA sufferers survive with a majority of these survivors emerging in a comatose state. Many CA survivors suffer devastating global brain injury with some remaining indefinitely in a comatose state. The pathogenesis of global brain injury secondary to CA is complex. Mechanisms of CA-induced brain injury include ischemia, hypoxia, cytotoxicity, inflammation, and ultimately, irreversible neuronal damage. Due to this complexity, it is critical for clinicians to have access as early as possible to quantitative metrics for diagnosing injury severity, accurately predicting outcome, and informing patient care. Current recommendations involve using multiple modalities including clinical exam, electrophysiology, brain imaging, and molecular biomarkers. This multi-faceted approach is designed to improve prognostication to avoid “self-fulfilling” prophecy and early withdrawal of life-sustaining treatments. Incorporation of emerging dynamic monitoring tools such as diffuse optical technologies may provide improved diagnosis and early prognostication to better inform treatment. Currently, targeted temperature management (TTM) is the leading treatment, with the number of patients needed to treat being ~ 6 in order to improve outcome for one patient. Future avenues of treatment, which may potentially be combined with TTM, include pharmacotherapy, perfusion/oxygenation targets, and pre/postconditioning. In this review, we provide a bench to bedside approach to delineate the pathophysiology, prognostication methods, current targeted therapies, and future directions of research surrounding hypoxic–ischemic brain injury (HIBI) secondary to CA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00856-z) contains supplementary material, which is available to authorized users.

Die neurologische Prognoseabschätzung nach kardiopulmonaler Reanimation ist ein medizinisch und ethisch herausfordernder Schritt in der Therapieplanung von Patienten nach Herzstillstand. Als Teil eines multimodalen diagnostischen Konzepts wird die zerebrale Bildgebung, insbesondere die Computertomographie empfohlen, wobei der ideale Zeitpunkt für die Durchführung dieser bisher unklar ist. Ein bereits etablierter Parameter zur Quantifizierung des globalen Hirnödems als Zeichen für hypoxisch-ischämische Enzephalopathie (HIE) ist die„Gray-White-Matter Ratio“ (GWR). Sie wird üblicherweise manuell von einem (Neuro)-Radiologen bestimmt, was das Problem der Inter-Rater-Variabilität mit sich bringt. Wir untersuchten zunächst an einer Registerkohorte den Zusammenhang zwischen Zeit und GWRVeränderungen um den Zeitpunkt und Grenzwert mit der besten prognostischen Aussagekraftder Bildgebung zu identifizieren. Daraufhin entwickelten wir für eine zweite Studie eine Methode, um die radiologischen Veränderungen in CTs automatisiert zu erfassen, verwendeten diese, um daraus den aussagekräftigsten prognostischen Parameter zu eruieren und validierten diesen an einer weiteren Kohorte. In einer multizentrischen Studie untersuchten wir schließlich retrospektiv in den histopathologisch aufgearbeiteten Gehirnen verstorbener Patienten den Schweregrad des hypoxischen Hirnschadens unter einem bestimmen GWR-Grenzwert. Wir erfassten das neurologische Outcome mit der Cerebral Performance Category (CPC) Skala bei Entlassung von der Intensivstation bzw. aus dem Krankenhaus, dichotomisiert in gutes (CPC 1-3) und schlechtes Outcome (CPC 4-5). Ergebnisse: Aus den in der ersten Studie eingeschlossenen 195 Patienten hatten kein Patient mit gutem Outcome eine (manuell bestimmte) GWR < 1.10. Die Sensitivität zur Vorhersage eines schlechten neurologischen Outcomes stieg von 12% bei CTs aus den ersten 6 Stunden nach Herzstillstand auf 48% für CTs, die später als 24 Stunden durchgeführt wurden. In die automatisierte Auswertung wurden 516 CTs von 433 Patienten eingeschlossen. In allen Regionen der grauen Substanz, insbesondere den Basalganglien war die Röntgendichte (in Hounsfield Units HU) bei Patienten mit schlechtem Outcome signifikant niedriger, in der weißen Substanz zeigte sich dies nicht. Die beste Vorhersagekraft hatte eine automatisierte GWR auf Ebene der Basalganglien (GWR_si). Auch hier stieg die Sensitivität innerhalb der ersten 72 Stunden deutlich an. Unter dem Grenzwert, After cardiac arrest (CA) and successful resuscitation, many patients suffer from severe hypoxicischemic encephalopathy (HIE). Prognostication of long-term neurological outcome is therefore an important step in deciding on therapeutic goals. Brain computed tomography (CT) is recommended by guidelines as part of a multimodal diagnostic pathway including serum biomarkers, clinical and electrophysiologic tests. The Gray-White-Matter Ratio (GWR) derived from CT quantifies global brain edema in patients with hypoxic-ischemic encephalopathy (HIE). Most studies report on GWR determined by a (neuro-)radiologist, a potential source of interrater variability. We evaluated brain CT as a prognostic tool in three separate studies: (I) We retrospectively examined the relationship between CT timing and GWR to identify the optimal timepoint and threshold with the best prognostic performance. (II) We developed a method to automatically quantify regional radiodensity changes by co-registration of individual head CT images with a brain atlas, identified the regions with best prognostic performance in a derivation cohort and validated the results in a validation cohort. (III) We histopathologically examined postmortem brain autopsies to assess if exams and cutoffs used for prognostication accurately reflect the underlying pathologies. Neurologic outcome was evaluated using the Cerebral Performance Scale (CPC) at ICU/hospital discharge, dichotomized in good (CPC 1-3) and poor (CPC 4-5) outcome. Results: Among 195 patients in the first study, no patient with good outcome patient had a (manually determined) GWR

Anoxic brain injury (ABI) is an important cause of prolonged hospital stay and morbidity across the globe. It is a sequel of major systemic insults resulting from various etiologies, such as reduced oxygen availability, insufficient cerebral blood flow, reduced oxygen carriage, or any metabolic condition that can interfere with the utilization of oxygen. A varying combination of pathophysiologic mechanisms leads to a spectrum of clinical manifestations, the understanding of which will significantly help in prognostication of patients. Neuroprognostication helps both the clinician and the patient's family in planning future course and is further aided by various neuromonitoring modalities, biomarkers, and imaging. Targeted temperature management still remains a therapeutic tool in ABI and along with other neuroprotective measures may improve the survival. Continuing research in ABI may uncover more promising treatment strategies.

Objectives: To assess ultra-early neuroprognostic significance of GFAP, NF-L, UCH-L1, tau, and S100B concentrations, change trajectory, and combination profile after Out-of-Hospital Cardiac Arrest (OHCA). Methods: Prospective enrollment of 22 OHCA and 10 control patients at an academic tertiary care center between May 1, 2017 and January 28, 2020. Blood was collected within one hour of return of spontaneous circulation (ROSC) (H0), at hours 6 (H6), 12, 18, 24, and daily or until discharge or death. Biomarker concentrations, multifactor score, and trajectory change were assessed and compared to final neurologic status (good vs poor Cerebral Performance Category; CPC 1–2 vs CPC 3–5, respectively). Results: 10 patients had good and 12 had poor neurologic outcomes. Poor outcome patients had higher biomarker concentrations and combined biomarker scores at early time points. The earliest significant difference between good and poor outcome patients’ serum biomarkers were at H12 for GFAP (good median: 425 pg/mL [IQR:370−630] vs poor: 5954[1712–65,055] pg/mL; p

Introduction: The aims of this study were to assess the concordance of different tools and to describe the accuracy of a multimodal approach to predict unfavorable neurological outcome (UO) in cardiac arrest patients. Methods: Retrospective study of adult (&gt, 18 years) cardiac arrest patients who underwent multimodal monitoring, UO was defined as cerebral performance category 3–5 at 3 months. Predictors of UO were neurological pupillary index (NPi) ≤2 at 24 h, highly malignant patterns on EEG (HMp) within 48 h, bilateral absence of N20 waves on somato-sensory evoked potentials, and neuron-specific enolase (NSE) &gt, 75 μg/L. Time-dependent decisional tree (i.e., NPi on day 1, HMp on day 1–2, absent N20 on day 2–3, highest NSE) and classification and regression tree (CART) analysis were used to assess the prediction of UO. Results: Of 137 patients, 104 (73%) had UO. Abnormal NPi, HMp on day 1 or 2, the bilateral absence of N20 or NSE&gt, 75 mcg/L had a specificity of 100% to predict UO. The presence of abnormal NPi was highly concordant with HMp and high NSE, and absence of N20 or high NSE with HMp. However, HMp had weak to moderate concordance with other predictors. The time-dependent decisional tree approach identified 73/103 patients (70%) with UO, showing a sensitivity of 71% and a specificity of 100%. Using the CART approach, HMp on EEG was the only variable significantly associated with UO. Conclusions: This study suggests that patients with UO had often at least two predictors of UO, except for HMp. A multimodal time-dependent approach may be helpful in the prediction of UO after CA. EEG should be included in all multimodal prognostic models.

Purpose: To evaluate serum S100 protein at hospital admission and after 48 h in early neuroprognostication of comatose survivors of out-of-hospital cardiac arrest (OHCA).Methods: The study included 48 consecutive patients after OHCA, who survived for at least 72 h after the event. The patients were divided based on their best cerebral performance category (CPC) achieved over a 30 day follow-up period: favorable neurological outcome (CPC 1–2) vs. unfavorable neurological outcome (CPC 3–4). Predictors of an unfavorable neurological outcome were identified by multivariable regression analysis. Analysis of the receiver operating characteristic curve (ROC) was used to determine the cut-off value for S100, having a 0% false-positive prediction rate.Results: Of the 48 patients, 30 (63%) had a favorable and 18 (38%) had an unfavorable neurological outcome. Eleven patients (23%) died over the 30 day follow-up. Increased S100 levels at 48 h after OHCA, but not the baseline S100 levels, were independently associated with unfavorable neurological outcome, with an area under the ROC curve of 0.85 (confidence interval 0.74–0.96). A 48 h S100 value ≥0.37 μg/L had a specificity of 100% and sensitivity of 39% in predicting an unfavorable 30 day neurological outcome.Conclusion: This study showed that S100 values assessed 48 h after an OHCA could independently predict an unfavorable neurological outcome at 30 days.

Supplemental Digital Content is available in the text., Objectives: End-of-life care and decisions on withdrawal of life-sustaining therapies vary across countries, which may affect the feasibility of future multicenter cardiac arrest trials. In Brazil, withdrawal of life-sustaining therapy is reportedly uncommon, allowing the natural history of postcardiac arrest hypoxic-ischemic brain injury to present itself. We aimed to characterize approaches to neuroprognostication of cardiac arrest survivors among physicians in Brazil. Design: Cross-sectional study. Setting: Between August 2, 2019, and July 31, 2020, we distributed a web-based survey to physicians practicing in Brazil. Subjects: Physicians practicing in Brazil and members of the Brazilian Association of Neurointensive Care, who care for patients resuscitated following cardiac arrest. Interventions: Not applicable. Measurements and Main Results: Responses from 185 physicians were obtained. Pupillary reflexes, corneal reflexes, and motor responses were considered critical to prognostication, whereas neuroimaging and electroencephalography were also regarded as important. For patients without targeted temperature management, absent pupillary and corneal reflexes at 24 hours postarrest were considered strongly predictive of poor neurologic outcome by 31.8% and 33.0%, respectively. For targeted temperature management-treated patients, absent pupillary and corneal reflexes at 24-hour postrewarming were considered prognostic by 22.9% and 20.0%, respectively. Physicians felt comfortable making definitive prognostic recommendations at day 6 postarrest or later (34.2%) for nontargeted temperature management-treated patients, and at day 6 postrewarming (20.4%) for targeted temperature management-treated patients. Over 90% believed that improving neuroprognostic accuracy would affect end-of-life decision-making. Conclusions: There is significant variability in neuroprognostic approaches to postcardiac arrest patients and timing of prognostic studies among Brazilian physicians, with practices frequently deviating from current guidelines, underscoring a need for greater neuroprognostic accuracy. Nearly all physicians believed that improving neuroprognostication will impact end-of-life decision-making. Given the tendency to delay prognostic recommendations while using similar neuroprognostic tools, Brazil offers a unique cohort in which to examine the natural history of hypoxic-ischemic brain injury in future studies.

International audience; Predicting the functional recovery of patients with severe neurological condition due to coronavirus disease 2019 (COVID-19) is a challenging task. Only limited outcome data are available, the pathophysiology is poorly understood, and the time-course of recovery is still largely unknown. Here, we report the case of a patient with COVID-19 associated encephalitis presenting as a prolonged state of unresponsiveness for two months, who finally fully recovered consciousness, functional communication, and autonomy after immunotherapy. In a multimodal approach, a high-density resting state EEG revealed a rich brain activity in spite of a severe clinical presentation. Using our previously validated algorithms, we could predict a possible improvement of consciousness in this patient. This case report illustrates the value of a multimodal approach capitalizing on advanced brain-imaging and bedside electrophysiology techniques to improve prognosis accuracy in this complex and new aetiology.

Background Current guidelines to predicting 'poor' neurological outcome in post-arrest unconscious adults have not previously been analysed in detail and, authoritative guidance to prediction of 'good' neuroprognosis does not exist. Methods A narrative appraisal of guideline statements and presented clinical indices of 'poor' neuroprognosis and, a systematic review of reported bedside indicators of 'good' outcome. Results The overall quality of neuroprognostication studies is low. Current neuroprognostication guidelines focus exclusively on predicting 'poor' outcome of post-CA unconsciousness by static clinical and/or paraclinical tests 3-5 days after ROSC and yield indirect evidence only. The approach is weakened also because acknowledged 'poor' outcome signs can be indistinguishable from features of natural brain revival towards intact neurological survival. Guidelines do not address 'good' outcome indicators. Twenty-one studies on 'good' outcome parameters were identified. Eleven were of low or very low quality of evidence and ten studies poorer. Inclusion of individuals about-to or already-awake presumably biased 12 studies. However, the order, recovery rate and linkage of clinical features seem essential for monitoring and predicting the brain resuscitation course after cardiopulmonary arrest. Unconscious patients likely to make 'good' recoveries can be discerned from those with 'poor' neuro-perspectives by cranial nerve reflex findings during BLS and within 60 min from ROSC or by the results of cranial nerve reflex-, motor responses to 'pain'- and EEG investigations within the first few hours from ROSC. Patient's neurological performances or quality of life scores at best after awakening seem rational prognostication endpoints. Conclusion Serial bedside investigations deployed within minutes to a few hours during unconsciousness and longitudinal surveillance of patient's neurological faculties and quality of life scores after awakening are suggested to improve neuroprognostication in adults resuscitated from cardiopulmonary arrest.

BackgroundNeuron-specific enolase (NSE) is a widely-used biomarker for prognostication of neurological outcome after cardiac arrest, but the relevance of recommended cutoff values has been questioned due to the lack of a standardized methodology and uncertainties over the influence of temperature management.ObjectivesThis study investigated the role of NSE as a prognostic marker of outcome after out-of-hospital cardiac arrest (OHCA) in a contemporary setting.MethodsA total of 686 patients hospitalized after OHCA were randomized to targeted temperature management at either 33°C or 36°C. NSE levels were assessed in blood samples obtained 24, 48, and 72 h after return of spontaneous circulation. The primary outcome was neurological outcome at 6 months using the cerebral performance category score.ResultsNSE was a robust predictor of neurological outcome in a baseline variable-adjusted model, and target temperature did not significantly affect NSE values. Median NSE values were 18 ng/ml versus 35 ng/ml, 15 ng/ml versus 61 ng/ml, and 12 ng/ml versus 54 ng/ml for good versus poor outcome at 24, 48, and 72 h, respectively (p < 0.001). At 48 and 72 h, NSE predicted neurological outcome with areas under the receiver-operating curve of 0.85 and 0.86, respectively. High NSE cutoff values with false positive rates ≤5% and tight 95% confidence intervals were able to reliably predict outcome.ConclusionsHigh, serial NSE values are strong predictors of poor outcome after OHCA. Targeted temperature management at 33°C or 36°C does not significantly affect NSE levels. (Target Temperature Management After Cardiac Arrest [TTM]; NCT01020916)

Background We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 °C and 36 °C) on serum levels of S100. Methods This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1–2 = good outcome, CPC 3–5 = poor outcome). Results We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10–0.49) versus 0.08 (IQR 0.06–0.11) μg/ml, 0.16 (IQR 0.10–0.44) versus 0.07 (IQR 0.06–0.11) μg/L, and 0.13 (IQR 0.08–0.26) versus 0.06 (IQR 0.05–0.09) μg/L (p

Background Serum biomarkers may play a role in prognostication after cardiac arrest. This study was designed to assess the feasibility of using two-dimensional gel electrophoresis (2D-GE) coupled with mass spectrometry (MS) as a proteomic strategy to identify novel biomarkers that may predict neurological recovery. Methods Adult comatose survivors of ventricular fibrillation or pulseless ventricular tachycardia were considered eligible. Blood was collected and serum separated within 6 h of hospital admission and then at 24 h afterwards. Neurological outcome was assessed at 3 months with the Cerebral Performance Category (CPC) score. Serum was assessed with 2D-GE with and without prior depletion of high abundance proteins. Protein differences between patients with good (CPC 1,2) vs. poor (CPC 3–5) neurological recovery were subsequently identified with MS. Results From August 2010 to June 2014, 11 patients meeting eligibility criteria were recruited, from which serum was available from 9 (5 with good neurological outcome). On non-depleted serum, only high abundance acute phase proteins such as haptoglobin, cell-free hemoglobin, albumin, and amyloid were detected in both patients with good and poor neurological recovery. Following depletion of high abundance proteins, proteins identified by MS in both patient populations were the acute phase reactants c-reactive protein and retinol binding protein-4. Proteins uniquely identified in the serum of patients with poor neurological recovery included 14-3-3 (epsilon and zeta isoforms) and muskelin. Conclusions Two-D-GE coupled with MS is a feasible strategy to facilitate the identification of novel predictive biomarkers. The presence of muskelin and 14-3-3 in the serum of patients with poor neurological prognosis warrants further investigation.