Modeling and Estimation of Cardiorespiratory Function, with Application to Mechanical Ventilation

Evidence-based medicine is at the heart of current medical practice where clinical decisions are driven by research data. However, most current therapy recommendations follow generalized protocols and guidelines that are based on epidemiological (population) studies and thus not suited for the individual patient's demands. Patient-tailored therapies are considered, hence, an unmet clinical need. We believe that mathematical models of the physiology can attend to such a clinical need, because they can be tuned to the individual patient. Such models provide a sound mathematical framework for personalized clinical decisions. In particular, physiological models in medicine can serve the following two purposes: 1) They can be an efficient tool to quantify cardiopulmonary dynamics, conduct virtual clinical/physiological experiments, and investigate the effects of specific treatments. 2) Model-based estimation techniques can assess physiological parameters or variables, which are otherwise impractical or dangerous to measure; they can effectively tune a generic model to become patient-specific, able to mimic the behavior of a particular patient. In this thesis, we propose a series of modifications to a previously developed cardiopulmonary model (CP Model) in order to better replicate heart-lung interaction phenomena that are typically observed under mechanical ventilation, hence allowing for a more accurate analysis of ventilation-induced changes in cardiac function. The response of this modified model is validated with experimental data collected during mechanical ventilation conditions. Further, as an industrial application of mathematical models, we present a patient emulator system that comprises the modified CP Model, a physical ventilator, and a piston-cylinder arrangement that serves as an electrical-to-hydraulic transducer. The modified CP Model then serves as the virtual patient that is being ventilated, where disease conditions can be instilled. Such a system is designed to offer a well-controlled experimental environment for ventilator manufacturers to efficaciously test and compare ventilation modalities and therapies, thereby enhancing their verification and validation manufacturing processes. Finally, we develop a model-based approach to estimate (noninvasively) the function of the cardiovascular system, in terms of cardiac performance (i.e., cardiac output) and the dynamics of the systemic arterial tree (i.e., time constant). With this technique, we envision to provide continuous and real-time bedside monitoring of changes in cardiovascular function, such as those induced by changes in ventilator settings

Physiology-based Mathematical Models for the Intensive Care Unit: Application to Mechanical Ventilation

This work takes us a step closer to realizing personalized medicine, complementing empirical and heuristic way in which clinicians typically work. This thesis presents mechanistic models of physiology. These models, given continuous signals from a patient, can be fine-tuned via parameter estimation methods so that the model's outputs match the patient's. We thus obtain a virtual patient mimicking the patient at hand. Therapeutic scenarios can then be applied and optimal diagnosis and therapy can thus be attained. As such, personalized medicine can then be achieved without resorting to costly genetics. In particular we have developed a novel comprehensive mathematical model of the cardiopulmonary system that includes cardiovascular circulation, respiratory mechanics, tissue and alveolar gas exchange, as well as short-term neural control. Validity of the model was proven by the excellent agreement with real patient data, under normo-physiological as well as hypercapnic and hypoxic conditions, taken from literature. As a concrete example, a submodel of the lung mechanics was fine-tuned using real patient data and personalized respiratory parameters (resistance, R_rs, and compliance, C_rs) were estimated continually. This allows us to compute the patient's effort (Work of Breathing), continuously and more importantly noninvasively. Finally, the use of Bayesian estimation techniques, which allow incorporation of population studies and prior information about model's parameters, was proposed in the contest of patient-specific physiological models. A Bayesian Maximum a Posteriori Probability (MAP) estimator was implemented and applied to a case-study of respiratory mechanics. Its superiority against the classical Least Squares method was proven in data-poor conditions using both simulated and real animal data. This thesis can serve as a platform for a plethora of applications for cardiopulmonary personalized medicine

Generation of Anatomically Inspired Human Airway Tree Using Electrical Impedance Tomography: A Method to Estimate Regional Lung Filling Characteristics

The purpose of lung recruitment is to improve and optimize the air exchange flow in the lungs by adjusting the respiratory settings during mechanical ventilation. Electrical impedance tomography (EIT) is a monitoring tool that allows to measure regional pulmonary filling characteristics or filling index (FI) during ventilation. The conventional EIT system has limitations which compromise the accuracy of the FI. This paper proposes a novel and automated methodology for accurate FI estimation based on EIT images of recruitable regional collapse and hyperdistension during incremental positive end-expiratory pressure. It identifies details of the airway tree (AT) to generate a correction factor to the FIs providing an accurate measurement. Multiscale image enhancement followed by identification of the AT skeleton with a robust and self-exploratory tracing algorithm is used to automatically estimate the FI. AT tracing was validated using phantom data on a ground-truth lung. Based on generated phantom EIT images, including an established reference, the proposed method results in more accurate FI estimation of 65% in all quadrants compared with the current state-of-the-art. Measured regional filling characteristics were also examined by comparing regional and global impedance variations in clinically recorded data from ten different subjects. Clinical tests on filling characteristics based on extraction of the AT from the resolution enhanced EIT images indicated a more accurate result compared with the standard EIT images

Breathing pattern characterization in patients with respiratory and cardiac failure

El objetivo principal de la tesis es estudiar los patrones respiratorios de pacientes en proceso de extubación y pacientes con insuficiencia cardiaca crónica (CHF), a partirde la señal de flujo respiratorio. La información obtenida de este estudio puede contribuir a la comprensión de los procesos fisiológicos subyacentes,y ayudar en el diagnóstico de estos pacientes. Uno de los problemas más desafiantes en unidades de cuidados intensivos es elproceso de desconexión de pacientes asistidos mediante ventilación mecánica. Más del 10% de pacientes que se extuban tienen que ser reintubados antes de 48 horas. Una prueba fallida puede ocasionar distrés cardiopulmonar y una mayor tasa de mortalidad. Se caracterizó el patrón respiratorio y la interacción dinámica entre la frecuenciacardiaca y frecuencia respiratoria, para obtener índices no invasivos que proporcionen una mayor información en el proceso de destete y mejorar el éxito de la desconexión.Las señales de flujo respiratorio y electrocardiográfica utilizadas en este estudio fueron obtenidas durante 30 minutos aplicando la prueba de tubo en T. Se compararon94 pacientes que tuvieron éxito en el proceso de extubación (GE), 39 pacientes que fracasaron en la prueba al mantener la respiración espontánea (GF), y 21 pacientes quesuperaron la prueba con éxito y fueron extubados, pero antes de 48 horas tuvieron que ser reintubados (GR). El patrón respiratorio se caracterizó a partir de las series temporales. Se aplicó la dinámica simbólica conjunta a las series correspondientes a las frecuencias cardiaca y respiratoria, para describir las interacciones cardiorrespiratoria de estos pacientes. Técnicas de "clustering", ecualización del histograma, clasificación mediante máquinasde soporte vectorial (SVM) y técnicas de validación permitieron seleccionar el conjunto de características más relevantes. Se propuso una nueva métrica B (índice de equilibrio) para la optimización de la clasificación con muestras desbalanceadas. Basado en este nuevo índice, aplicando SVM, se seleccionaron las mejores características que mantenían el mejor equilibrio entre sensibilidad y especificidad en todas las clasificaciones. El mejor resultado se obtuvo considerando conjuntamente la precisión y el valor de B, con una clasificación del 80% entre los grupos GE y GF, con 6 características. Clasificando GE vs. el resto de los pacientes, el mejor resultado se obtuvo con 9 características, con 81%. Clasificando GR vs. GE y GR vs. el resto de pacientes la precisión fue del 83% y 81% con 9 y 10 características, respectivamente. La tasa de mortalidad en pacientes con CHF es alta y la estratificación de estospacientes en función del riesgo es uno de los principales retos de la cardiología contemporánea. Estos pacientes a menudo desarrollan patrones de respiraciónperiódica (PB) incluyendo la respiración de Cheyne-Stokes (CSR) y respiración periódica sin apnea. La respiración periódica en estos pacientes se ha asociadocon una mayor mortalidad, especialmente en pacientes con CSR. Por lo tanto, el estudio de estos patrones respiratorios podría servir como un marcador de riesgo y proporcionar una mayor información sobre el estado fisiopatológico de pacientes con CHF. Se pretende identificar la condición de los pacientes con CHFde forma no invasiva mediante la caracterización y clasificación de patrones respiratorios con PBy respiración no periódica (nPB), y patrón de sujetos sanos, a partir registros de 15minutos de la señal de flujo respiratorio. Se caracterizó el patrón respiratorio mediante un estudio tiempo-frecuencia estacionario y no estacionario, de la envolvente de la señal de flujo respiratorio. Parámetros relacionados con la potencia espectral de la envolvente de la señal presentaron losmejores resultados en la clasificación de sujetos sanos y pacientes con CHF con CSR, PB y nPB. Las curvas ROC validan los resultados obtenidos. Se aplicó la "correntropy" para una caracterización tiempo-frecuencia mas completa del patrón respiratorio de pacientes con CHF. La "corretronpy" considera los momentos estadísticos de orden superior, siendo más robusta frente a los "outliers". Con la densidad espectral de correntropy (CSD) tanto la frecuencia de modulación como la dela respiración se representan en su posición real en el eje frecuencial. Los pacientes con PB y nPB, presentan diferentesgrados de periodicidad en función de su condición, mientras que los sujetos sanos no tienen periodicidad marcada. Con único parámetro se obtuvieron resultados del 88.9% clasificando pacientes PB vs. nPB, 95.2% para CHF vs. sanos, 94.4% para nPB vs. sanos.The main objective of this thesis is to study andcharacterize breathing patterns through the respiratory flow signal applied to patients on weaning trials from mechanicalventilation and patients with chronic heart failure (CHF). The aim is to contribute to theunderstanding of the underlying physiological processes and to help in the diagnosis of these patients. One of the most challenging problems in intensive care units is still the process ofdiscontinuing mechanical ventilation, as over 10% of patients who undergo successfulT-tube trials have to be reintubated in less than 48 hours. A failed weaning trial mayinduce cardiopulmonary distress and carries a higher mortality rate. We characterize therespiratory pattern and the dynamic interaction between heart rate and breathing rate toobtain noninvasive indices that provide enhanced information about the weaningprocess and improve the weaning outcome. This is achieved through a comparison of 94 patients with successful trials (GS), 39patients who fail to maintain spontaneous breathing (GF), and 21 patients who successfully maintain spontaneous breathing and are extubated, but require thereinstitution of mechanical ventilation in less than 48 hours because they are unable tobreathe (GR). The ECG and the respiratory flow signals used in this study were acquired during T-tube tests and last 30 minute. The respiratory pattern was characterized by means of a number of respiratory timeseries. Joint symbolic dynamics applied to time series of heart rate and respiratoryfrequency was used to describe the cardiorespiratory interactions of patients during theweaning trial process. Clustering, histogram equalization, support vector machines-based classification (SVM) and validation techniques enabled the selection of the bestsubset of input features. We defined a new optimization metric for unbalanced classification problems, andestablished a new SVM feature selection method, based on this balance index B. The proposed B-based SVM feature selection provided a better balance between sensitivityand specificity in all classifications. The best classification result was obtained with SVM feature selection based on bothaccuracy and the balance index, which classified GS and GFwith an accuracy of 80%, considering 6 features. Classifying GS versus the rest of patients, the best result wasobtained with 9 features, 81%, and the accuracy classifying GR versus GS, and GR versus the rest of the patients was 83% and 81% with 9 and 10 features, respectively.The mortality rate in CHF patients remains high and risk stratification in these patients isstill one of the major challenges of contemporary cardiology. Patients with CHF oftendevelop periodic breathing patterns including Cheyne-Stokes respiration (CSR) and periodic breathing without apnea. Periodic breathing in CHF patients is associated withincreased mortality, especially in CSR patients. Therefore it could serve as a risk markerand can provide enhanced information about thepathophysiological condition of CHF patients. The main goal of this research was to identify CHF patients' condition noninvasively bycharacterizing and classifying respiratory flow patterns from patients with PB and nPBand healthy subjects by using 15-minute long respiratory flow signals. The respiratory pattern was characterized by a stationary and a nonstationary time-frequency study through the envelope of the respiratory flow signal. Power-related parameters achieved the best results in all of the classifications involving healthy subjects and CHF patients with CSR, PB and nPB and the ROC curves validated theresults obtained for the identification of different respiratory patterns. We investigated the use of correntropy for the spectral characterization of respiratory patterns in CHF patients. The correntropy function accounts for higher-order moments and is robust to outliers. Due to the former property, the respiratory and modulationfrequencies appear at their actual locations along the frequency axis in the correntropy spectral density (CSD). The best results were achieved with correntropy and CSD-related parameters that characterized the power in the modulation and respiration discriminant bands, definedas a frequency interval centred on the modulation and respiration frequency peaks,respectively. All patients, i.e. both PB and nPB, exhibit various degrees of periodicitydepending on their condition, whereas healthy subjects have no pronounced periodicity.This fact led to excellent results classifying PB and nPB patients 88.9%, CHF versushealthy 95.2%, and nPB versus healthy 94.4% with only one parameter.Postprint (published version

Comportamento temporal da DPOC e influência do confinamento imposto pela COVID-19: comparação de métodos de seleção de variáveis

Modelling a certain outcome is challenging and it is common practice to collect several features in that attempt. Nevertheless, the appropriate statistical methods to select important and meaningful features are still unknown, namely under repeated measurements Longitudinal data can be grouped in forming trajectories that can be altered by countless factors, some of them unexpected. Identifying individuals’ outcome trajectories at early stage of illness, as well as potential risk factors should be of high priority since this knowledge can guide to the development of individually tailored treatment and result in effective interventions. Chronic obstructive pulmonary disease is a progressive and preventable disease and people with this disease could benefit from the identification of such risk factors and over time behaviour. In this dissertation we aimed to compare different feature selection methods based on regression algorithms, namely, random forest, Boruta, extreme gradient boosting, L-1 penalized estimation and automatic backward selection, adapted to longitudinal data. We also aimed to describe the effect of the Coronavirus disease 2019 lockdown on the one-minute sit-to-stand test, handgrip muscle strength and chronic obstructive pulmonary disease assessment test behaviour. We finally aimed to explore the factors influencing the behaviour of the one-minute sit-to-stand test over a six-month period in people with chronic obstructive pulmonary disease. We showed that the automatic backward elimination of features was consistent when it came to select statistically relevant features to be included in linear mixed-effects models with the lowest values of Akaike information criterion. The COVID-19 lockdown period seemed to have had no effect in the one-minute sit-to-stand test and handgrip muscle strength behaviour but a negative effect in the impact of the disease was observed. Also, an increase of the smoking load or age seems to lead to a worse evolution in the one-minute sit-to-stand test results over time in people with chronic obstructive pulmonary disease.Modelar um determinado resultado é desafiante e recorre-se habitualmente à recolha de diversas variáveis. Contudo, desconhecem-se ainda os métodos estatísticos apropriados para a seleção de variáveis importantes e com significado, nomeadamente em dados longitudinais. Dados longitudinais podem ser agrupados e definem trajetórias alteráveis por inúmeros fatores, alguns deles inesperados. Identificar as trajetórias individuais de determinados resultados em fases iniciais de uma doença, bem como os potenciais fatores de risco, deveria ser prioritário uma vez que esse conhecimento pode conduzir ao desenvolvimento de tratamentos individualizados e resultar em intervenções efetivas. A doença pulmonar obstrutiva crónica é uma doença prevenível e progressiva e indivíduos com esta doença poderiam beneficiar com a identificação desses fatores de risco e do comportamento da doença ao longo do tempo. Esta dissertação teve como objetivos comparar diferentes métodos de seleção de variáveis, em dados longitudinais, baseados em algoritmos de regressão, nomeadamente, random forest, Boruta, extreme gradient boosting, estimação com penalização L-1 e eliminação automática. Também pretendemos descrever o efeito provocado pelo confinamento decorrente da pandemia de COVID-19 no teste de sentar e levantar em 1 minuto, na força de preensão manual e no teste de avaliação do impacto da doença pulmonar obstrutiva crónica. Finalmente, explorámos os fatores que influenciam o comportamento do teste de sentar e levantar em 1 minuto ao longo de seis meses em indivíduos com doença pulmonar obstrutiva crónica. O método de eliminação automática foi consistente na seleção de variáveis que produziram modelos lineares de efeitos mistos com menores valores de critério de informação de Akaike. O período de confinamento não teve efeito estatisticamente significativo no teste de sentar e levantar em 1 minuto nem na força de preensão manual. No entanto, foi observado um efeito negativo no impacto da doença. Foi também observada uma pior evolução dos resultados do teste de sentar e levantar em 1 minuto, ao longo do tempo, em indivíduos com doença pulmonar obstrutiva crónica mais velhos e com maior carga tabágica.Mestrado em Estatística Médic

Exploiting Temporal Image Information in Minimally Invasive Surgery

Minimally invasive procedures rely on medical imaging instead of the surgeons direct vision. While preoperative images can be used for surgical planning and navigation, once the surgeon arrives at the target site real-time intraoperative imaging is needed. However, acquiring and interpreting these images can be challenging and much of the rich temporal information present in these images is not visible. The goal of this thesis is to improve image guidance for minimally invasive surgery in two main areas. First, by showing how high-quality ultrasound video can be obtained by integrating an ultrasound transducer directly into delivery devices for beating heart valve surgery. Secondly, by extracting hidden temporal information through video processing methods to help the surgeon localize important anatomical structures. Prototypes of delivery tools, with integrated ultrasound imaging, were developed for both transcatheter aortic valve implantation and mitral valve repair. These tools provided an on-site view that shows the tool-tissue interactions during valve repair. Additionally, augmented reality environments were used to add more anatomical context that aids in navigation and in interpreting the on-site video. Other procedures can be improved by extracting hidden temporal information from the intraoperative video. In ultrasound guided epidural injections, dural pulsation provides a cue in finding a clear trajectory to the epidural space. By processing the video using extended Kalman filtering, subtle pulsations were automatically detected and visualized in real-time. A statistical framework for analyzing periodicity was developed based on dynamic linear modelling. In addition to detecting dural pulsation in lumbar spine ultrasound, this approach was used to image tissue perfusion in natural video and generate ventilation maps from free-breathing magnetic resonance imaging. A second statistical method, based on spectral analysis of pixel intensity values, allowed blood flow to be detected directly from high-frequency B-mode ultrasound video. Finally, pulsatile cues in endoscopic video were enhanced through Eulerian video magnification to help localize critical vasculature. This approach shows particular promise in identifying the basilar artery in endoscopic third ventriculostomy and the prostatic artery in nerve-sparing prostatectomy. A real-time implementation was developed which processed full-resolution stereoscopic video on the da Vinci Surgical System

Understanding Peripheral Blood Pressure Signals: A Statistical Learning Approach

Proper estimation of body fluid status for human or animal subjects has always been a challenging problem. Accurate and timely estimate of body fluid can prevent life threatening conditions under trauma and severe dehydration. The main objective of this research is the estimation, classification and detection of dehydration in human and animal subjects using peripheral blood pressure (PBP) signals. Peripheral venous pressure (PVP) and peripheral arterial pressure (PAP) signals have been investigated in this research. Both PVP and PAP signals are PBP signals. A dataset of PVP signals was collected using standard peripheral intravenous catheters from human subjects suffering from hypertrophic pyloric stenosis. Using this dataset, we successfully classified dehydrated subjects from hydrated subjects using regularized logistic regression on frequency domain data of the PVP signals. During the data acquisition process, the PVP signals was corrupted by noise and blood clot. So, we developed an unsupervised anomaly detection algorithm for PVP signals using hidden Markov model and Kalman filter. This anomaly detection algorithm removed the human bias in data-preprocessing. Another dataset of PAP and PVP signals was collected from pigs under anesthesia using the Millar catheter. We proposed a integral pulse frequency modulation (IPFM) based signal model for both PAP and PVP signals. The proposed model-synthesized signal is highly correlated with the experimental data. The model-synthesized signals also performs similar to experimental signals under classification tasks. We also examine the model estimated parameters both qualitatively and quantitatively. This model can also quantify the effect of respiratory rate on heart rate variability. Increasing doses of anesthesia has similar effect of getting hydrated from dehydration