A Physiology-Driven Computational Model for Post-Cardiac Arrest Outcome Prediction

Patients resuscitated from cardiac arrest (CA) face a high risk of neurological disability and death, however pragmatic methods are lacking for accurate and reliable prognostication. The aim of this study was to build computational models to predict post-CA outcome by leveraging high-dimensional patient data available early after admission to the intensive care unit (ICU). We hypothesized that model performance could be enhanced by integrating physiological time series (PTS) data and by training machine learning (ML) classifiers. We compared three models integrating features extracted from the electronic health records (EHR) alone, features derived from PTS collected in the first 24hrs after ICU admission (PTS24), and models integrating PTS24 and EHR. Outcomes of interest were survival and neurological outcome at ICU discharge. Combined EHR-PTS24 models had higher discrimination (area under the receiver operating characteristic curve [AUC]) than models which used either EHR or PTS24 alone, for the prediction of survival (AUC 0.85, 0.80 and 0.68 respectively) and neurological outcome (0.87, 0.83 and 0.78). The best ML classifier achieved higher discrimination than the reference logistic regression model (APACHE III) for survival (AUC 0.85 vs 0.70) and neurological outcome prediction (AUC 0.87 vs 0.75). Feature analysis revealed previously unknown factors to be associated with post-CA recovery. Results attest to the effectiveness of ML models for post-CA predictive modeling and suggest that PTS recorded in very early phase after resuscitation encode short-term outcome probabilities.Comment: 51 pages, 7 figures, 4 supplementary figure

Electrographic signatures of postanoxic brain injury

After a successful resuscitation from cardiac arrest, most patients remain comatose as a result of postanoxic encephalopathy. More than half of them never regain consciousness, and treatment options to improve their outcome are limited. The aim of the research described in this dissertation was to validate and improve the value of continuous electroencephalography (EEG) for outcome prediction and treatment of postanoxic brain injury. In a prospective cohort study of 850 patients, we confirmed that EEG reaches its maximum value for the prediction of outcome within the first 24 hours after cardiac arrest. The added value of continuous EEG monitoring beyond this period was limited. Generalized suppression (all EEG activity <10 µV) or synchronous patterns with more than 50% suppression reliably predicted a poor outcome at 12h after cardiac arrest or later. Continuous background activity within 12h from cardiac arrest was a strong predictor of good outcome. To make the assessment of postanoxic EEG less time-consuming and more objective, we introduced straightforward quantitative EEG features, based on key aspects of visual assessment for the prediction of outcome. Our measures for background continuity and amplitude fluctuation were at least as sensitive for the prediction of good outcome as visual assessment, at equal reliability. In the subgroup of patients with electrographic seizure activity, we showed that a lack of background continuity of the EEG precludes recovery. During the first 24 hours after cardiac arrest, the most valuable period for the prediction of outcome, patients are usually treated with sedative medication. We showed quantitatively that propofol, a commonly applied sedative drug, changes the postanoxic EEG, but does not affect its reliability for the prediction of outcome. A better understanding of mechanisms that underlie postanoxic EEG patterns could validate associations between EEG and outcome, and offer opportunities for new treatment strategies. By using a computational model, we showed that pathophysiological changes at the synaptic level explain the most commonly observed EEG patterns after cardiac arrest and their evolution. Finally, we present the study protocol of the ongoing, randomized TELSTAR trial on the treatment of electrographic status epilepticus after cardiac arrest

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI

Artificial intelligence for clinical decision support for monitoring patients in cardiovascular ICUs: a systematic review

Background: Artificial intelligence (AI) and machine learning (ML) models continue to evolve the clinical decision support systems (CDSS). However, challenges arise when it comes to the integration of AI/ML into clinical scenarios. In this systematic review, we followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA), the population, intervention, comparator, outcome, and study design (PICOS), and the medical AI life cycle guidelines to investigate studies and tools which address AI/ML-based approaches towards clinical decision support (CDS) for monitoring cardiovascular patients in intensive care units (ICUs). We further discuss recent advances, pitfalls, and future perspectives towards effective integration of AI into routine practices as were identified and elaborated over an extensive selection process for state-of-the-art manuscripts. Methods: Studies with available English full text from PubMed and Google Scholar in the period from January 2018 to August 2022 were considered. The manuscripts were fetched through a combination of the search keywords including AI, ML, reinforcement learning (RL), deep learning, clinical decision support, and cardiovascular critical care and patients monitoring. The manuscripts were analyzed and filtered based on qualitative and quantitative criteria such as target population, proper study design, cross-validation, and risk of bias. Results: More than 100 queries over two medical search engines and subjective literature research were developed which identified 89 studies. After extensive assessments of the studies both technically and medically, 21 studies were selected for the final qualitative assessment. Discussion: Clinical time series and electronic health records (EHR) data were the most common input modalities, while methods such as gradient boosting, recurrent neural networks (RNNs) and RL were mostly used for the analysis. Seventy-five percent of the selected papers lacked validation against external datasets highlighting the generalizability issue. Also, interpretability of the AI decisions was identified as a central issue towards effective integration of AI in healthcare

Deep learning for EEG-based prognostication after cardiac arrest: from current research to future clinical applications.

Outcome prognostication in comatose patients after cardiac arrest (CA) remains to date a challenge. The major determinant of clinical outcome is the post-hypoxic/ischemic encephalopathy. Electroencephalography (EEG) is routinely used to assess neural functions in comatose patients. Currently, EEG-based outcome prognosis relies on visual evaluation by medical experts, which is time consuming, prone to subjectivity, and oblivious to complex patterns. The field of deep learning has given rise to powerful algorithms for detecting patterns in large amounts of data. Analyzing EEG signals of coma patients with deep neural networks with the goal of assisting in outcome prognosis is therefore a natural application of these algorithms. Here, we provide the first narrative literature review on the use of deep learning for prognostication after CA. Existing studies show overall high performance in predicting outcome, relying either on spontaneous or on auditory evoked EEG signals. Moreover, the literature is concerned with algorithmic interpretability, and has shown that largely, deep neural networks base their decisions on clinically or neurophysiologically meaningful features. We conclude this review by discussing considerations that the fields of artificial intelligence and neurology will need to jointly address in the future, in order for deep learning algorithms to break the publication barrier, and to be integrated in clinical practice

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

Quantitative Ventricular Fibrillation Metrics in a Biosignal Guided Cardiopulmonary Resuscitation Device for Cardiac Arrest and Their Translation to Clinical Data

Out of hospital cardiac arrest is a major cause of mortality with an estimated yearly incidence of 350,000 in the United States alone. Cardiopulmonary resuscitation (CPR) is a treatment for cardiac arrest involving chest compressions and rescues breaths that can save lives but is limited by the fact that it currently treats all patients in a 'one size fits all' approach. This work describes an adaptive approach to chest compressions controlled by a mechanical device that receives biosignals from the patient it treats. The device is capable of adjusting its chest compression parameters such as rate and depth in response to the biosignals it receives. We focused on integrating the quantitative electrocardiogram (QECG) of the ventricular fibrillation signal, a biosignal shown to respond to increased perfusion of the myocardium during CPR, into a chest compression algorithm controlled by the adaptive chest compression device. QECG is readily available for cardiac arrest patients since ECG analysis is standard of care in cardiac arrest. In our first aim we developed the adaptive chest compression device and tested it in animal feasibility studies which demonstrated that it responded appropriately to the biosignals it received. Next, in a computational model of adaptive chest compressions, adjustments in chest compression depth yielded the largest increase in cardiac output in patients with simulated variable physiology. In follow-up animal studies, select QECG measures responded to changes in chest compression parameters which demonstrated the initial feasibility of QECG measures as a potential biosignal in this model. We found that the QECG measures of median slope, centroid frequency, and log of the absolute correlation responded to changes in chest compression rate in the early phase of chest compressions. We found that in late phases of chest compressions the QECG measure median slope responded to chest compression rate changes and the QECG measure AMSA responded to chest compression duty cycle changes. Our second aim sought to retrospectively translate the findings in the first aim animal studies to human clinical data in the continuous chest compression trial of the Resuscitation Outcomes Consortium (ROC). The clinical trial provided us with ECG and compression data in covering thousands of cardiac arrest events. All QECG metrics in the clinical data set was predictive of shock outcome and chest compression rate along with chest compression bout duration were predictive of survival. However, when controlled for the presenting first rhythm status and demographic variables, only chest compression bout duration was predictive of survival. In addition to the predictive value of chest compression parameters and QECG measures, associations were found between varying chest compression parameters averaged across bouts of compressions with change in QECG values (dQECG) in the clinical data. Chest compression rate was found to be predictive of the dQECG metric median slope (dMS) and the dQECG metric (dAMSA). Dosed compression rate was found to be predictive of the dQECG metric dMS as well. dCF responded to changes in chest compression duty cycle. These findings provide a foundation for delivering adaptive chest compressions with the potential of improving survival outcomes to cardiac arrest

Cardiac Arrhythmias

Cardiac arrhythmias are common triggers of emergency admission to cardiology or high-dependency departments. Most cases are easy to diagnose and treat, while others may present a challenge to healthcare professionals. A translational approach to arrhythmias links molecular and cellular scientific research with clinical diagnostics and therapeutic methods, which may include both pharmacological and non-pharmacologic treatments. This book presents a comprehensive overview of specific cardiac arrhythmias and discusses translational approaches to their diagnosis and treatment

A Comparison of Intensive Care Unit Mortality Prediction Models through the Use of Data Mining Techniques

OBJECTIVES: The intensive care environment generates a wealth of critical care data suited to developing a well-calibrated prediction tool. This study was done to develop an intensive care unit (ICU) mortality prediction model built on University of Kentucky Hospital (UKH)\u27s data and to assess whether the performance of various data mining techniques, such as the artificial neural network (ANN), support vector machine (SVM) and decision trees (DT), outperform the conventional logistic regression (LR) statistical model. METHODS: The models were built on ICU data collected regarding 38,474 admissions to the UKH between January 1998 and September 2007. The first 24 hours of the ICU admission data were used, including patient demographics, admission information, physiology data, chronic health items, and outcome information. RESULTS: Only 15 study variables were identified as significant for inclusion in the model development. The DT algorithm slightly outperformed (AUC, 0.892) the other data mining techniques, followed by the ANN (AUC, 0.874), and SVM (AUC, 0.876), compared to that of the APACHE III performance (AUC, 0.871). CONCLUSIONS: With fewer variables needed, the machine learning algorithms that we developed were proven to be as good as the conventional APACHE III prediction