Towards patient-specific modelling as a pre-operative planning strategy and follow up assessment for the treatment of advanced heart failure with rotary blood pumps

Background: Ventricular Assist Devices (VADs) insertion is an established treatment for patients with end-stage heart failure waiting for a heart transplant or in need for long-term circulatory support (destination therapy). Rotary blood pumps (RBP) are the most popular devices in view of their size and performance. Pre-operative planning strategy for the insertion of a left ventricular assist device (LVAD) requires a timely discussion at a Multi-Disciplinary Team Meeting (MDT). Clinical-decision making is based according to the needs of the patient and must be processed without delays. Nevertheless, thrombus formation remains a feared complication which affects outcome. VADs operate in a flow regime which is difficult to simulate: the transitional region at the boundary of laminar and turbulent flow (low Reynolds number). Different methods have been used but the best approach remains debatable. Computational Fluid Dynamics (CFD) is an attractive and invaluable tool for the study of the interactions between VADs and the cardiovascular system. The aim of this thesis is three-fold: a) to investigate the use of pressure-volume analysis in a clinical setting through the review of six heart failure patients previously discussed at a MDT meeting with a view to predict or guide further management; b) to review the theory behind modelling approaches to VADs and their interactions with the cardiovascular system for better understanding of their clinical use. Then, an overview of computational fluid dynamics (CFD) is considered as a prelude to its application to the analysis of VADs performance. Additionally, the development of a simplified model of centrifugal pump will be used in initial simulations as preliminary analysis; c) to examine an example of a proof-of-concept pilot patient-specific model of an axial flow pump (HeartMate II) as pre-operative planning strategy in a patient-specific model with a view to identify potential critical areas that may affect pump function and outcome in a clinical setting. Material and Methods: 3D reconstruction from CT-scan images of patients who underwent the insertion of rotary blood pumps, namely HeartWare HVAD and HeartMate II. Ansys Fluent has been used for CFD analysis based on the fundamental governing equations of motion. Blood has been modelled as incompressible, Newtonian fluid with density = 1060 and viscosity = 0.0035 kg/m-s. The laminar and SST models have been used for comparison purposes. The rotational motion of the impeller has been implemented using the moving reference frame (MRF) approach. The sliding mesh method has also been used to account for unsteady interaction between stationary and moving part. The no-slip condition has been applied to all walls, which were assumed to be rigid. Boundary conditions consisting of velocity inlet and pressure outlet of the pump based on different settings and constant rotational speed for the impeller. Pressure-velocity coupling has been based on the coupled scheme. Spatial discretisation consisted of the “least square cell based” gradient for velocity and “PRESTO” or second order for pressure. Second order upwind has been set for the momentum, turbulent kinetic energy and specific dissipation rate. First order implicit has been set for transient formulation. The pseudo transient algorithm (steady state), the high order relaxation term and the warped-face gradient correction have been used to add an unsteady term to the solution equations with the aim to improve stability and enhance convergence. Specific settings have been considered for comparison purposes. Results: Pressure-volume simulation analysis in six advanced heart failure patients showed that an integrated model of the cardiovascular system based on lumped-parameter representation, modified time-varying elastance and pressure-volume analysis of ventricular function seems a feasible and suitable approach yielding a sufficiently accurate quantitative analysis in real time, therefore applicable within the time-constraints of a clinical setting. Lumped-parameter models consist of simultaneous ordinary differential equations complemented by an algebraic balance equation and are suitable for examination of global distribution of pressure, flow and volume over a range of physiological conditions with inclusion of the interaction between modelled components. Higher level lumped-parameter modelling is needed to address the interaction between the circulation and other systems based on a compromise between complexity and ability to set the required parameters to personalise an integrated lumped-parameter model for a patient-specific approach. CARDIOSIM© fulfils these requirements and does address the systems interaction with its modular approach and assembly of models with varying degree of complexity although 0-D and 1-D coupling may be required for the evaluation of long-term VAD support. The challenge remains the ability to predict outcome over a longer period of time. The preliminary CFD simulations with the HeartWare HVAD centrifugal pump demonstrated that it is possible to obtain an accurate analysis in a timely manner to complement the clinical review process. The simulations with the pilot patient-specific model of the HeartMate II axial flow pump revealed that a complex 3D reconstruction is feasible in a timely manner and can be used to generate sufficiently accurate results to be used in the context of a MDT meeting for the purposes of clinical decision-making. Overall, these three studies demonstrate that the time frame of the simulations was within hours which may fit the time constraints of the clinical environment in the context of a MDT meeting. More specifically, it was shown that the laminar model may be used for an initial evaluation of the flow development within the pump. Nonetheless, the k- model offers higher accuracy if the timeline of the clinical setting allows for a longer simulation. Conclusion: This thesis aimed at the understanding of the use of computational modelling as a pre-operative planning strategy and follow up assessment for the treatment of advanced heart failure with rotary blood pumps. The novelty lays in the use of both pressure-volume simulation analysis and 3D flow dynamics studies in VADs with a view to treatment optimisation and outcome prediction within the time constraints of a clinical setting in the context of a MDT meeting. The clinical significance and the contribution to the field is a more targeted approach for different groups of patients and a more quantitative evaluation in the clinical decision process based on a pro-active co-operation between clinicians and scientists reducing the potential for “guess work”. The results of this thesis are a proof-of-concept as a prelude to a potential future implementation of patient-specific modelling within a clinical setting on a daily basis demonstrating a clear clinical significance and contribution to the field. The proposed approach does not consider modelling and simulation as a substitute for clinical experience but an additional tool to guide therapeutic intervention and complement the clinical decision process in which the clinician remains the ultimate decision-maker. Such an approach may well add a different dimension to the problem of heart failure with potential for high return in terms of patient’s outcome and long-term surveillance. The same principles would be applicable to other cardiovascular problems in line with the current concept of “Team Approach” such as the Heart Team, the Structural Heart Team or the Aortic Team. The present work has taken this concept closer to clinical delivery and has highlighted its potential but further work remains to be done in refining the technique.Background: Ventricular Assist Devices (VADs) insertion is an established treatment for patients with end-stage heart failure waiting for a heart transplant or in need for long-term circulatory support (destination therapy). Rotary blood pumps (RBP) are the most popular devices in view of their size and performance. Pre-operative planning strategy for the insertion of a left ventricular assist device (LVAD) requires a timely discussion at a Multi-Disciplinary Team Meeting (MDT). Clinical-decision making is based according to the needs of the patient and must be processed without delays. Nevertheless, thrombus formation remains a feared complication which affects outcome. VADs operate in a flow regime which is difficult to simulate: the transitional region at the boundary of laminar and turbulent flow (low Reynolds number). Different methods have been used but the best approach remains debatable. Computational Fluid Dynamics (CFD) is an attractive and invaluable tool for the study of the interactions between VADs and the cardiovascular system. The aim of this thesis is three-fold: a) to investigate the use of pressure-volume analysis in a clinical setting through the review of six heart failure patients previously discussed at a MDT meeting with a view to predict or guide further management; b) to review the theory behind modelling approaches to VADs and their interactions with the cardiovascular system for better understanding of their clinical use. Then, an overview of computational fluid dynamics (CFD) is considered as a prelude to its application to the analysis of VADs performance. Additionally, the development of a simplified model of centrifugal pump will be used in initial simulations as preliminary analysis; c) to examine an example of a proof-of-concept pilot patient-specific model of an axial flow pump (HeartMate II) as pre-operative planning strategy in a patient-specific model with a view to identify potential critical areas that may affect pump function and outcome in a clinical setting. Material and Methods: 3D reconstruction from CT-scan images of patients who underwent the insertion of rotary blood pumps, namely HeartWare HVAD and HeartMate II. Ansys Fluent has been used for CFD analysis based on the fundamental governing equations of motion. Blood has been modelled as incompressible, Newtonian fluid with density = 1060 and viscosity = 0.0035 kg/m-s. The laminar and SST models have been used for comparison purposes. The rotational motion of the impeller has been implemented using the moving reference frame (MRF) approach. The sliding mesh method has also been used to account for unsteady interaction between stationary and moving part. The no-slip condition has been applied to all walls, which were assumed to be rigid. Boundary conditions consisting of velocity inlet and pressure outlet of the pump based on different settings and constant rotational speed for the impeller. Pressure-velocity coupling has been based on the coupled scheme. Spatial discretisation consisted of the “least square cell based” gradient for velocity and “PRESTO” or second order for pressure. Second order upwind has been set for the momentum, turbulent kinetic energy and specific dissipation rate. First order implicit has been set for transient formulation. The pseudo transient algorithm (steady state), the high order relaxation term and the warped-face gradient correction have been used to add an unsteady term to the solution equations with the aim to improve stability and enhance convergence. Specific settings have been considered for comparison purposes. Results: Pressure-volume simulation analysis in six advanced heart failure patients showed that an integrated model of the cardiovascular system based on lumped-parameter representation, modified time-varying elastance and pressure-volume analysis of ventricular function seems a feasible and suitable approach yielding a sufficiently accurate quantitative analysis in real time, therefore applicable within the time-constraints of a clinical setting. Lumped-parameter models consist of simultaneous ordinary differential equations complemented by an algebraic balance equation and are suitable for examination of global distribution of pressure, flow and volume over a range of physiological conditions with inclusion of the interaction between modelled components. Higher level lumped-parameter modelling is needed to address the interaction between the circulation and other systems based on a compromise between complexity and ability to set the required parameters to personalise an integrated lumped-parameter model for a patient-specific approach. CARDIOSIM© fulfils these requirements and does address the systems interaction with its modular approach and assembly of models with varying degree of complexity although 0-D and 1-D coupling may be required for the evaluation of long-term VAD support. The challenge remains the ability to predict outcome over a longer period of time. The preliminary CFD simulations with the HeartWare HVAD centrifugal pump demonstrated that it is possible to obtain an accurate analysis in a timely manner to complement the clinical review process. The simulations with the pilot patient-specific model of the HeartMate II axial flow pump revealed that a complex 3D reconstruction is feasible in a timely manner and can be used to generate sufficiently accurate results to be used in the context of a MDT meeting for the purposes of clinical decision-making. Overall, these three studies demonstrate that the time frame of the simulations was within hours which may fit the time constraints of the clinical environment in the context of a MDT meeting. More specifically, it was shown that the laminar model may be used for an initial evaluation of the flow development within the pump. Nonetheless, the k- model offers higher accuracy if the timeline of the clinical setting allows for a longer simulation. Conclusion: This thesis aimed at the understanding of the use of computational modelling as a pre-operative planning strategy and follow up assessment for the treatment of advanced heart failure with rotary blood pumps. The novelty lays in the use of both pressure-volume simulation analysis and 3D flow dynamics studies in VADs with a view to treatment optimisation and outcome prediction within the time constraints of a clinical setting in the context of a MDT meeting. The clinical significance and the contribution to the field is a more targeted approach for different groups of patients and a more quantitative evaluation in the clinical decision process based on a pro-active co-operation between clinicians and scientists reducing the potential for “guess work”. The results of this thesis are a proof-of-concept as a prelude to a potential future implementation of patient-specific modelling within a clinical setting on a daily basis demonstrating a clear clinical significance and contribution to the field. The proposed approach does not consider modelling and simulation as a substitute for clinical experience but an additional tool to guide therapeutic intervention and complement the clinical decision process in which the clinician remains the ultimate decision-maker. Such an approach may well add a different dimension to the problem of heart failure with potential for high return in terms of patient’s outcome and long-term surveillance. The same principles would be applicable to other cardiovascular problems in line with the current concept of “Team Approach” such as the Heart Team, the Structural Heart Team or the Aortic Team. The present work has taken this concept closer to clinical delivery and has highlighted its potential but further work remains to be done in refining the technique

Heart Rate Variability – A Historical Perspective

Heart rate variability (HRV), the beat-to-beat variation in either heart rate or the duration of the R–R interval – the heart period, has become a popular clinical and investigational tool. The temporal fluctuations in heart rate exhibit a marked synchrony with respiration (increasing during inspiration and decreasing during expiration – the so called respiratory sinus arrhythmia, RSA) and are widely believed to reflect changes in cardiac autonomic regulation. Although the exact contributions of the parasympathetic and the sympathetic divisions of the autonomic nervous system to this variability are controversial and remain the subject of active investigation and debate, a number of time and frequency domain techniques have been developed to provide insight into cardiac autonomic regulation in both health and disease. It is the purpose of this essay to provide an historical overview of the evolution in the concept of HRV. Briefly, pulse rate was first measured by ancient Greek physicians and scientists. However, it was not until the invention of the “Physician’s Pulse Watch” (a watch with a second hand that could be stopped) in 1707 that changes in pulse rate could be accurately assessed. The Rev. Stephen Hales (1733) was the first to note that pulse varied with respiration and in 1847 Carl Ludwig was the first to record RSA. With the measurement of the ECG (1895) and advent of digital signal processing techniques in the 1960s, investigation of HRV and its relationship to health and disease has exploded. This essay will conclude with a brief description of time domain, frequency domain, and non-linear dynamic analysis techniques (and their limitations) that are commonly used to measure HRV

A Unified Point Process Probabilistic Framework to Assess Heartbeat Dynamics and Autonomic Cardiovascular Control

In recent years, time-varying inhomogeneous point process models have been introduced for assessment of instantaneous heartbeat dynamics as well as specific cardiovascular control mechanisms and hemodynamics. Assessment of the model’s statistics is established through the Wiener-Volterra theory and a multivariate autoregressive (AR) structure. A variety of instantaneous cardiovascular metrics, such as heart rate (HR), heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and baroreceptor-cardiac reflex (baroreflex) sensitivity (BRS), are derived within a parametric framework and instantaneously updated with adaptive and local maximum likelihood estimation algorithms. Inclusion of second-order non-linearities, with subsequent bispectral quantification in the frequency domain, further allows for definition of instantaneous metrics of non-linearity. We here present a comprehensive review of the devised methods as applied to experimental recordings from healthy subjects during propofol anesthesia. Collective results reveal interesting dynamic trends across the different pharmacological interventions operated within each anesthesia session, confirming the ability of the algorithm to track important changes in cardiorespiratory elicited interactions, and pointing at our mathematical approach as a promising monitoring tool for an accurate, non-invasive assessment in clinical practice. We also discuss the limitations and other alternative modeling strategies of our point process approach

Refined Multiscale Fuzzy Entropy to Analyse Post-Exercise Cardiovascular Response in Older Adults With Orthostatic Intolerance

[EN] Orthostatic intolerance syndrome occurs when the autonomic nervous system is incapacitated and fails to respond to the demands associated with the upright position. Assessing this syndrome among the elderly population is important in order to prevent falls. However, this problem is still challenging. The goal of this work was to determine the relationship between orthostatic intolerance (OI) and the cardiovascular response to exercise from the analysis of heart rate and blood pressure. More specifically, the behavior of these cardiovascular variables was evaluated in terms of refined composite multiscale fuzzy entropy (RCMFE), measured at different scales. The dataset was composed by 65 older subjects, 44.6% (n = 29) were OI symptomatic and 55.4% (n = 36) were not. Insignificant differences were found in age and gender between symptomatic and asymptomatic OI participants. When heart rate was evaluated, higher differences between groups were observed during the recovery period immediately after exercise. With respect to the blood pressure and other hemodynamic parameters, most significant results were obtained in the post-exercise stage. In any case, the symptomatic OI group exhibited higher irregularity in the measured parameters, as higher RCMFE levels in all time scales were obtained. This information could be very helpful for a better understanding of cardiovascular instability, as well as to recognize risk factors for falls and impairment of functional status.This research was funded by the Ministerio de Economia y Competitividad from the Spanish Government, through its research program Programa Estatal de I+D+i Orientada a los Retos de la Sociedad, grant number DPI2015-70821-R.Hortelano, M.; Reilly, R.; Castells, F.; Cervigón, R. (2018). Refined Multiscale Fuzzy Entropy to Analyse Post-Exercise Cardiovascular Response in Older Adults With Orthostatic Intolerance. Entropy. 20(11):1-12. https://doi.org/10.3390/e20110860S112201

Novel Framework for Nonlinear HRV Analysis and its Physiological Interpretation

La inclusión de métodos no lineales aplicados a señales de variabilidad del ritmo cardiaco (HRV, del inglés Heart Rate Variability) proporciona una nueva visión en la caracterización de anomalías en el contexto de las enfermedades cardiacas o patologías como la insuficiencia cardiaca o la fibrilación auricular, por nombrar algunas. Se ha demostrado que alteraciones en el sistema nervioso autónomo (ANS, del inglés Autonomic Nervous System), el cuál modula el ritmo cardiaco, conllevan a cambios en los patrones no lineales de la HRV. Sin embargo, la incertidumbre, todavía presente, en los mecanismos que subyacen a variaciones fisiológicas o patofisiológicas en los índices no lineales de la HRV, junto con el alto tiempo que requieren los algoritmos para la estimación de estos índices, representan el cuello de botella para su aplicación en la práctica clínica.Después de una breve introducción sobre los temas abordados en esta la tesis en el capítulo 1, el segundo capítulo, el capítulo 2, está dedicado a la primera gran contribución de esta tesis, que consiste en la propuesta y desarrollo de una metodología con el fin de reducir el coste computacional asociado a la caracterización no lineal de la HRV. El esquema propuesto es muy eficaz, reduciendo el tiempo de cálculo a unos pocos segundos para el análisis no lineal de señales de HRV de corta longitud (5 minutos). Con respecto a la interpretación del análisis no lineal de la HRV, es importante señalar que hay una serie de factores que afectan a su cálculo y deben tenerse en cuenta al comparar diferentes estudios de la literatura. Las características de las series de HRV, como la frecuencia de muestreo, así como la selección de valores de parámetros en los métodos no lineales, tienen un impacto en los resultados de los índices no lineales de la HRV y, en algunas circunstancias, pueden dar lugar a interpretaciones erróneas. Uno de los principales objetivos del capítulo 3 es estudiar la influencia de la tasa de muestreo en los índices no lineales de la HRV y proponer alternativas para atenuar esta influencia. Los métodos propuestos incluyen, por una parte, la corrección de la frecuencia cardiaca de las estimaciones de la HRV mediante fórmulas de regresión individuales o basadas en la población y, por otra, el preprocesamiento de las series temporales de HRV mediante modelos de interpolación o de point-process. El capítulo 4 se centra en investigar el efecto de la selección del valor de los parámetros requeridos para el cálculo de ciertos índices no lineales de la HRV (por ejemplo, la entropía aproximada) y proponiendo un nuevo índice independiente de la definición del valor de éstos parámetros a-priori. Este novedoso índice se denomina entropía multidimensional aproximada. El análisis no lineal de la HRV, incluido el nuevo índice propuesto, se aplica al estudio de afecciones asociadas a alteraciones de la modulación cardiaca del ANS, como el envejecimiento y la insuficiencia cardiaca congestiva (CHF, del inglés Congestive Heart Failure). Por un lado, todos los índices no lineales de la HRV evaluados ven disminuidos significativamente sus valores en las personas mayores en comparación con los jóvenes ambos grupos en condiciones de reposo en posición de decubito supino. Por otro lado, los pacientes con insuficiencia cardiaca muestran valores más altos de los índices no lineales significativamente con respecto al grupo de sujetos sanos, en ambos casos analizando el período nocturno. Además, el análisis no lineal de la HRV es evaluada en respuesta a provocaciones simpáticas, inducidas por el cambio de la posición supina a la posición de pie o por la administración de atropina, donde se observa una disminución en todos los índicesno lineales estimados.El capítulo 5 está dedicado a la evaluación del rendimiento del análisis no lineal de la HRV en el triaje de la administración profiláctica con el fin de prevenir los episodios de hipotension causados por la anestesia espinal durante el parto por cesárea. El estudio se realiza en colaboración con el Servicio de Anestesia del Hospital Universitario Miguel Servet (Zaragoza, España). Debido a que la profilaxis puede producir efectos secundarios en el feto, el desafío consiste en predecir los casos normotensos para los cuales se puede prescindir del tratamiento profilactico. La hipótesis de esta tesis se basa en el hecho de que la alteración de la regulación del ANS causada por el último período de embarazo y la proximidad a la cirugía podría reflejarse en los índices no lineales de la HRV, lo que podría ayudar a predecir los casos que deriven en hipotension y normotension con mayor precisión que cuando se utilizan solamente variables demográficas. Es importante destacar que las propuestas metodológicas para el análisis no lineal de la HRV desarrolladas en la tesis se aplican en la caracterización de otras señales cardiovasculares, como la señal fotopletismografica de pulso. Las series temporales derivadas de esta señal, que incluyen información del sistema vascular periférico, se incorporan en un clasificador basado en la regresión logística junto con los índices no lineales de la HRV. El clasificador propuesto alcanza un 76,5% de sensibilidad y un 72,2% de precisión en la detección de los casos normotensos, proporcionando así información pertinente y objetiva respaldando la decisión final del equipo médico.En el capítulo 6 se presentan las principales conclusiones derivadas de la tesis y se consideran futuras ampliaciones en base a las investigaciones llevadas a cabo. Se hace hincapié en la contribución de la tesis al desarrollo de metodologías novedosas para caracterizar de manera más robusta los índices no lineales de la HRV e interpretar con fiabilidad los resultados correspondientes. Basándose en las metodologías desarrolladas, se investigan las condiciones o patologías asociadas con alteraciones en la modulación autonómica de la actividad cardiaca y se destaca la contribución del análisis no lineal de la HRV para su caracterización. En conclusión, entre los objetivos metodológicos desarrollados en esta tesis se encuentran: i) la propuesta de un esquema de trabajo para incrementar la fiabilidad de la estimación de la dimensión de correlación, usando un algoritmo que reduce la carga computacional, facilitando su aplicabilidad en la práctica clínica; ii) el desarrollo de métodos alternativos para atenuar la dependencia de los índices no lineales de la HRV con el ritmo cardiaco medio; iii) la propuesta de un índice no lineal de la HRV multidimensional independiente de la definición a priori de parámetros para su estimación. Además, los objetivos relacionados con la aplicación clínica de lascontribuciones metodológicas son: i) la caracterización del efecto del envejecimiento en los índices no lineales de la HRV; ii) la evaluación de la complejidad e irregularidad del ritmo cardiaco en pacientes que sufren de insuficiencia cardiaca comparada con sujetos sanos; iii) la mejora de la eficacia de la profilaxis para la prevención de eventos de hipotensión después de anestesia espinal durante parto programado por cesárea.<br /

Beyond the Baroreflex: A New Measure of Autonomic Regulation Based on the Time-Frequency Assessment of Variability, Phase Coherence and Couplings

For decades the role of autonomic regulation and the baroreflex in the generation of the respiratory sinus arrhythmia (RSA) - modulation of heart rate by the frequency of breathing - has been under dispute. We hypothesized that by using autonomic blockers we can reveal which oscillations and their interactions are suppressed, elucidating their involvement in RSA as well as in cardiovascular regulation more generally. R-R intervals, end tidal CO2, finger arterial pressure, and muscle sympathetic nerve activity (MSNA) were measured simultaneously in 7 subjects during saline, atropine and propranolol infusion. The measurements were repeated during spontaneous and fixed-frequency breathing, and apnea. The power spectra, phase coherence and couplings were calculated to characterise the variability and interactions within the cardiovascular system. Atropine reduced R-R interval variability (p \u3c 0.05) in all three breathing conditions, reduced MSNA power during apnea and removed much of the significant coherence and couplings. Propranolol had smaller effect on the power of oscillations and did not change the number of significant interactions. Most notably, atropine reduced R-R interval power in the 0.145–0.6 Hz interval during apnea, which supports the hypothesis that the RSA is modulated by a mechanism other than the baroreflex. Atropine also reduced or made negative the phase shift between the systolic and diastolic pressure, indicating the cessation of baroreflex-dependent blood pressure variability. This result suggests that coherent respiratory oscillations in the blood pressure can be used for the non-invasive assessment of autonomic regulation

Pattern Analysis of Oxygen Saturation Variability in Healthy Individuals: Entropy of Pulse Oximetry Signals Carries Information about Mean Oxygen Saturation

Pulse oximetry is routinely used for monitoring patients' oxygen saturation levels with little regard to the variability of this physiological variable. There are few published studies on oxygen saturation variability (OSV), with none describing the variability and its pattern in a healthy adult population. The aim of this study was to characterize the pattern of OSV using several parameters; the regularity (sample entropy analysis), the self-similarity [detrended fluctuation analysis (DFA)] and the complexity [multiscale entropy (MSE) analysis]. Secondly, to determine if there were any changes that occur with age. The study population consisted of 36 individuals. The “young” population consisted of 20 individuals [Mean (±1 SD) age = 21.0 (±1.36 years)] and the “old” population consisted of 16 individuals [Mean (±1 SD) age = 50.0 (±10.4 years)]. Through DFA analysis, OSV was shown to exhibit fractal-like patterns. The sample entropy revealed the variability to be more regular than heart rate variability and respiratory rate variability. There was also a significant inverse correlation between mean oxygen saturation and sample entropy in healthy individuals. Additionally, the MSE analysis described a complex fluctuation pattern, which was reduced with age (p < 0.05). These findings suggest partial “uncoupling” of the cardio-respiratory control system that occurs with aging. Overall, this study has characterized OSV using pre-existing tools. We have showed that entropy analysis of pulse oximetry signals carries information about body oxygenation. This may have the potential to be used in clinical practice to detect differences in diseased patient subsets

Effects of slow and regular breathing exercise on cardiopulmonary coupling and blood pressure

Investigation of the interaction between cardiovascular variables and respiration provides a quantitative and noninvasive approach to assess the autonomic control of cardiovascular function. The aim of this paper is to investigate the changes of cardiopulmonary coupling (CPC), blood pressure (BP) and pulse transit time (PTT) during a stepwise-paced breathing (SPB) procedure (spontaneous breathing followed by paced breathing at 14, 12.5, 11, 9.5, 8 and 7 breaths per minute, 3 min each) and gain insights into the characteristics of slow breathing exercises. RR interval, respiration, BP and PTT are collected during the SPB procedure (48 healthy subjects, 27 ± 6 years). CPC is assessed through investigating both the phase and amplitude dynamics between the respiration-induced components from RR interval and respiration by the approach of ensemble empirical mode decomposition. It was found that even though the phase synchronization and amplitude oscillation of CPC were both enhanced by the SPB procedure, phase coupling does not increase monotonically along with the amplitude oscillation during the whole procedure. Meanwhile, BP was reduced significantly by the SPB procedure (SBP: from 122.0 ± 13.4 to 114.2 ± 14.9 mmHg, p < 0.001, DBP: from 82.2 ± 8.6 to 77.0 ± 9.8 mmHg, p < 0.001, PTT: from 172.8 ± 20.1 to 176.8 ± 19.2 ms, p < 0.001). Our results demonstrate that the SPB procedure can reduce BP and lengthen PTT significantly. Compared with amplitude dynamics, phase dynamics is a different marker for CPC analysis in reflecting cardiorespiratory coherence during slow breathing exercise. Our study provides a methodology to practice slow breathing exercise, including the setting of target breathing rate, change of CPC and the importance of regular breathing. The applications and usability of the study results have also been discussed.National Natural Science Foundation (China) (Grant Number: 61471398)Beijing Natural Science Foundation (Grant Number: 3122034)General Logistics Science Foundation (Grant Number: CWS11C108)National Key Technology Research and Development Program (Grant Numbers: 2013BAI03B04, 2013BAI03B05

Breathing Signature as Vitality Score Index Created by Exercises of Qigong: Implications of Artificial Intelligence Tools Used in Traditional Chinese Medicine.

Rising concerns about the short- and long-term detrimental consequences of administration of conventional pharmacopeia are fueling the search for alternative, complementary, personalized, and comprehensive approaches to human healthcare. Qigong, a form of Traditional Chinese Medicine, represents a viable alternative approach. Here, we started with the practical, philosophical, and psychological background of Ki (in Japanese) or Qi (in Chinese) and their relationship to Qigong theory and clinical application. Noting the drawbacks of the current state of Qigong clinic, herein we propose that to manage the unique aspects of the Eastern 'non-linearity' and 'holistic' approach, it needs to be integrated with the Western "linearity" "one-direction" approach. This is done through developing the concepts of "Qigong breathing signatures," which can define our life breathing patterns associated with diseases using machine learning technology. We predict that this can be achieved by establishing an artificial intelligence (AI)-Medicine training camp of databases, which will integrate Qigong-like breathing patterns with different pathologies unique to individuals. Such an integrated connection will allow the AI-Medicine algorithm to identify breathing patterns and guide medical intervention. This unique view of potentially connecting Eastern Medicine and Western Technology can further add a novel insight to our current understanding of both Western and Eastern medicine, thereby establishing a vitality score index (VSI) that can predict the outcomes of lifestyle behaviors and medical conditions

Advanced analyses of physiological signals and their role in Neonatal Intensive Care

Preterm infants admitted to the neonatal intensive care unit (NICU) face an array of life-threatening diseases requiring procedures such as resuscitation and invasive monitoring, and other risks related to exposure to the hospital environment, all of which may have lifelong implications. This thesis examined a range of applications for advanced signal analyses in the NICU, from identifying of physiological patterns associated with neonatal outcomes, to evaluating the impact of certain treatments on physiological variability. Firstly, the thesis examined the potential to identify infants at risk of developing intraventricular haemorrhage, often interrelated with factors leading to preterm birth, mechanical ventilation, hypoxia and prolonged apnoeas. This thesis then characterised the cardiovascular impact of caffeine therapy which is often administered to prevent and treat apnoea of prematurity, finding greater pulse pressure variability and enhanced responsiveness of the autonomic nervous system. Cerebral autoregulation maintains cerebral blood flow despite fluctuations in arterial blood pressure and is an important consideration for preterm infants who are especially vulnerable to brain injury. Using various time and frequency domain correlation techniques, the thesis found acute changes in cerebral autoregulation of preterm infants following caffeine therapy. Nutrition in early life may also affect neurodevelopment and morbidity in later life. This thesis developed models for identifying malnutrition risk using anthropometry and near-infrared interactance features. This thesis has presented a range of ways in which advanced analyses including time series analysis, feature selection and model development can be applied to neonatal intensive care. There is a clear role for such analyses in early detection of clinical outcomes, characterising the effects of relevant treatments or pathologies and identifying infants at risk of later morbidity