The distributed computer system

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University

A Computational, Topological Approach to ICU Mortality Rate Prediction with Data Relationship Realization

The objective of this work is to predict the mortality of intensive care unit patients based on their physiological data and understand the relationships between physiological data. Such a model may be used to prioritize care when resources are limited or identify patients that will need significant care in the immediate future. This effort will take a novel approach applying computational topological analysis to classify patients. The algorithm predicting the patient outcomes is trained using an evolutionary algorithm. The dataset used is from the 2012 PhysioNet Computing in Cardiology Challenge. A set containing 4000 records with outcomes was used to train and test the prediction algorithm. The topology extraction algorithm, Mapper, was used to represent the high dimensional data as a 1-D graph of the set topology using a filter. The filter is trained using an evolutionary algorithm to maximize the positive prediction rate and sensitivity. The Event 1 score is the minimum of these two. This algorithm yielded an Event 1 score of 0.42 out of 1.00 for the PhysioNet Challenge. This is comparable to a currently used ICU classification system, SAPS-1 that achieved an event 1 score of 0.30. Additional developments from this work include an optimized Mapper clustering function that runs in 120 seconds for the complete data set compared to the 2.2 month estimate using the original function. This allowed the rapid iteration needed for optimization in this algorithm. The algorithm developed in this thesis could be more generally applied to analysis and prediction in any feature space for generic problems

Pharmacokinetic/pharmacodynamic relationship of pulmonary administration methods for milrinone : a translational approach

Suite à l'interruption de la circulation extracorporelle (CEC) chez les patients qui subissent une chirurgie cardiaque, le rétablissement de la circulation sanguine au niveau du poumon cause souvent une hypertension pulmonaire qui, à son tour, peut engendrer des complications au cœur droit. Pour traiter cette hypertension, la milrinone, un inhibiteur de la phosphodiestérase 3 (PDEIII) est souvent donnée par voie intraveineuse. Par contre, cette administration cause également une hypotension systémique qui peut nécessiter l’administration d'agents vasoactifs. Une administration de la milrinone par nébulisation a donc été adoptée, ciblant ainsi directement les poumons [1]. En cas d'urgence, la milrinone peut être injectée ou atomisée directement au niveau de la trachée. Lors de chirurgies cardiaques nécessitant une CEC, un protocole expérimental s'avère souvent difficile à respecter chez le patient. En effet, les contraintes temporelles, les nombreux médicaments co-administrés et le stress physique causé par la chirurgie sont autant de facteurs qui peuvent biaiser une étude dont le but est caractériser l’effet pharmacologique de la milrinone. Il s'est donc avéré important, en premier lieu, de quantifier les effets des artéfacts reliés aux manipulations chirurgicales sur notre biomarqueur, soit le ratio de la pression systémique moyenne sur la pression pulmonaire moyenne. Chez le porc, nous avons observé des changements de 30-50% au niveau des pressions systémiques moyennes, soit le double des changements au niveau des pressions pulmonaires pour le même artéfact. La durée moyenne de tous les effets, des artéfacts, (au niveau systémique et pulmonaire conjointement) fut de 4.5±2.5 min (n=152). Dû au biais potentiel apporté par ces artéfacts, l’utilisation d’un modèle animal dépourvu de manipulations chirurgicales s’est avérée être pleinement justifiée. En second lieu, la voie pulmonaire étant une voie d'administration non homologuée pour la milrinone, le site optimal de déposition pulmonaire permettant un effet local maximal n’a pas été identifié. La milrinone cible la PDEIII au niveau des muscles lisses vasculaires. Ainsi, l’effet anti-hypertensif local de la milrinone se situe au niveau des artères musculaires côtoyant l’arbre trachéobronchique. Nos études se concentrent sur les nébulisations par simple jet (SJ), par mèche vibrante (VM) ainsi que sur les administrations d’urgence, soit l’instillation (ITI) et l’atomisation (ITA) intratrachéale. De ce fait, nous avons conduit des études in vitro pour caractériser la taille des particules générée par les deux formes de nébulisation, qui est un facteur influençant la déposition pulmonaire. Nous avons aussi tenté, grâce à des études in et ex vivo, de démontrer une différence d’efficacité entre les deux méthodes de nébulisation. Les études in vitro ont permis, de quantifier la dose se rendant au poumon, soit la dose inhalée, et ont démontré une différence au niveau de la distribution de la taille des particules des gouttelettes générées par les deux nébulisations. Les résultats indiquent une taille de particules plus fine, visant préférentiellement la zone alvéolaire pour la nébulisation par mèche vibrante. Ils indiquent aussi une plus grande dose inhalée pour la nébulisation par mèche vibrante mais de façon surprenante, en tenant compte de la dose inhalée par le patient, une meilleure relaxation pulmonaire par simple jet. En plus d’une meilleure oxygénation suite à l’administration de la milrinone, nos études démontrent une sensibilité de 20 fois plus grande, tel que démontrée par le IC50 de la relaxation à l’acétylcholine, et un effet de relaxation près de 25% supérieur chez la nébulisation par simple jet En troisième lieu, la relation pharmacocinétique (PK) et pharmacodynamie (PD) de la milrinone par nébulisation n'a pas été caractérisée en absence d’artéfacts chirurgicaux et encore moins pour les voies d’urgence. Suite au développement d’un modèle d’hypertension pulmonaire sans manipulations chirurgicales, nous avons déterminé une relation concentration/effet (PK/PD) pour les méthodes d’administration pulmonaire et comparé leurs efficacités après correction pour la dose réellement inhalée, déterminée par collecte urinaire. Cette dernière étude démontre un EC50 de l’impact de la milrinone sur le ratio des pressions artérielles systémiques moyennes sur les pressions artérielles pulmonaires plus faible suite à l’administration de la milrinone par simple jet ainsi qu’une augmentation de ce ratio de près 40%. Les résultats obtenus au cours de ces études suggèrent l’administration par simple jet semble plus efficace. Par conséquent, un meilleur jugement clinique pourra être appliqué lors de la méthode d’administration ainsi que de la dose utilisée de la milrinone.Following weaning from cardiopulmonary bypass (CPB), the cardiac surgery patients undergoing a procedure are often faced with the pulmonary reperfusion syndrome which may lead to pulmonary hypertension condition which, in turn, is likely to precipitate right ventricular dysfunction. Milrinone, a phosphodiesterase type 3 inhibitor (PDEIII) is used, among others, to facilitate CPB weaning in patients by reducing the severity of pulmonary hypertension through vasodilation. Milrinone is typically given intravenously. However, this mode of administration is frequently associated with systemic hypotension which may require administration of vasoactive agents. Administration of milrinone throughnebulization has therefore been developed, targeting the lungs directly and avoiding systemic hypotension. In case of emergency, milrinone may even be injected directly into the trachea or even possibly atomized intratrachealy. In this thesis we will describe an experimental protocol where the administration of milrinone through inhalation was studied. Unfortunately, experimental protocols during surgeries requiring CPB are often challenging due to time and procedural constraints. Indeed, the signal-to-noise ratio makes it difficult to isolate the effect of a specific intervention. The effect of the other administered medications and the physical stress of surgery may result in potentially incomplete or biased pharmacological studies. This aspect is the basis of the first portion of the thesis. The identification and and the quantification of the surgical manipulation artifacts on our main biomarker, the mean systemic pressure over the mean pulmonary pressure, was our first objective. In our first study, following our experimentation, we witnessed a 30- 50% changes on systemic pressures and these changes were twice those observed on pulmonary pressures for the same artefact. Pooled durations of all effects on both mAP and mPAP averaged 4.5±2.5 min (n=152). These changes fully justified the creation of a new model due to the potential biais of the artefacts. Secondly, as nebulization is a novel way to administer milrinone, the pharmacokinetic-pharmacodynamics (PK-PD) relationship has not been completely characterized. Even less information is available for the emergency routes. Milrinone targets PDEIII in vascular smooth muscle, thus the local antihypertensive effect of milrinone is most likely to occur at the level of muscular arteries alongside the tracheobronchial tree. We studied four methods of administration: simple jet (SJ), vibrating mesh (VM) nebulization, intratracheal instillation (ITI) and atomization (ITA). In addition, the optimal pulmonary deposition and absorption site for maximum local effect remains as of yet unknown. We have strived to identify the factors influencing the lung deposition of milrinone through nebulization and part of the work discussed in this thesis is aimed at characterizing the amount of milrinone deposited on the various sections of the tracheobronchial tree by the mentioned methods. Through in and ex vivo studies we have investigated the differences in efficacy of the two nebulization methods. We have found each method to generate a significantly different deposition pattern and as such, influencing lung deposition. Our results show that VM targets the lower airways and alveoli, whereas SJ targets preferably the higher and middle airways. Our study also shows a higher inhaled dose for VM but surprisingly a better dose-related efficacy for SJ. Indeed, in addition to a better oxygenation, our study shows, as demonstrated by the acetylcholine-induced relaxation IC50, a 20 times higher sensitivity and a 25% higher maximum relaxation following simple jet nebulization. Subsequently, following the development of a pulmonary hypertension model devoid of surgical manipulations and, by association, artefacts, we have determined a urinary-dose-corrected PK/PD relationship for the nebulization and emergency methods of milrinone administration. We explored the methods of intratracheal bolus and atomization and compared their efficacy to those of nebulization. This study shows a lower EC50 of milrinone impact and an almost 40% increase of the mean systemic arterial pressure over mean pulmonary arterial pressures ratio following simple jet adminstration. The information obtained by these studies offers the potential to aid clinicians in making a more informed judgment in the use of milrinone

Parallel alogorithms for MIMD parallel computers

This thesis mainly covers the design and analysis of asynchronous parallel algorithms that can be run on MIMD (Multiple Instruction Multiple Data) parallel computers, in particular the NEPTUNE system at Loughborough University. Initially the fundamentals of parallel computer architectures are introduced with different parallel architectures being described and compared. The principles of parallel programming and the design of parallel algorithms are also outlined. Also the main characteristics of the 4 processor MIMD NEPTUNE system are presented, and performance indicators, i.e. the speed-up and the efficiency factors are defined for the measurement of parallelism in a given system. Both numerical and non-numerical algorithms are covered in the thesis. In the numerical solution of partial differential equations, a new parallel 9-point block iterative method is developed. Here, the organization of the blocks is done in such a way that each process contains its own group of 9 points on the network, therefore, they can be run in parallel. The parallel implementation of both 9-point and 4- point block iterative methods were programmed using natural and redblack ordering with synchronous and asynchronous approaches. The results obtained for these different implementations were compared and analysed. Next the parallel version of the A.G.E. (Alternating Group Explicit) method is developed in which the explicit nature of the difference equation is revealed and exploited when applied to derive the solution of both linear and non-linear 2-point boundary value problems. Two strategies have been used in the implementation of the parallel A.G.E. method using the synchronous and asynchronous approaches. The results from these implementations were compared. Also for comparison reasons the results obtained from the parallel A.G.E. were compared with the ~ corresponding results obtained from the parallel versions of the Jacobi, Gauss-Seidel and S.O.R. methods. Finally, a computational complexity analysis of the parallel A.G.E. algorithms is included. In the area of non-numeric algorithms, the problems of sorting and searching were studied. The sorting methods which were investigated was the shell and the digit sort methods. with each method different parallel strategies and approaches were used and compared to find the best results which can be obtained on the parallel machine. In the searching methods, the sequential search algorithm in an unordered table and the binary search algorithms were investigated and implemented in parallel with a presentation of the results. Finally, a complexity analysis of these methods is presented. The thesis concludes with a chapter summarizing the main results

Investigation of the baroreflex of the rat : steady state and dynamic features

The baroreflex is one of the most important feedback systems in the body to maintain blood pressure variation within the homeostatic range. In this dissertation, the important features of the carotid and aortic baroreflexes have been extensively investigated on ventilated, central nervous system intact, neuromuscular blocked (NMB) rats using different control system and signal processing tools. Studies have demonstrated that sinoaortic denervation (SAD) caused substantial increases in the blood pressure variability. Comparing the pre- and post-SAD blood pressure spectra, there was a significant increase of power in the very low frequency region (0.00195 -0.2 Hz), and a significant decrease of power in the low frequency region (0.2 - 0.6 Hz) after SAD. The dominant power change after SAD was in the very low frequency region of the blood pressure spectra. The carotid and aortic baroreflexes were accessed by volumetric manipulation of the carotid sinus and electrical manipulation of the aortic depressor nerve (ADN) using step and sinusoidal stimulations. Myelinated ADN-A fibers and myelinated + unmyelinated ADN-A+C fibers were accessed separately in the experiments. Results showed that the baroreflex functions as a \u27low-pass\u27 filter, with -3dB cutoff frequency at approximately \u3c0. I Hz. The major working area of the baroreflex system is in the VLF region of the blood pressure spectra. The estimated system transportation lag was 1.07s, which would cause the baroreflex system to oscillate at frequencies around 0.4 Hz. Analyses demonstrated that it is not likely that the baroreflex is activated only occasionally, such as in response to postural shifts, but operates continuously to bring the blood pressure into balance. It is theoretically and experimentally demonstrated that the absolute gain of the open-loop baroreflex system can be predicted by the ratio of the pre-and post- blood pressure amplitude spectra