Positive pressure mechanical ventilation (MV) has been utilised in the care of critically ill patients for over 50 years. MV essentially provides for oxygen delivery and carbon dioxide removal by the lungs in patient with respiratory failure or insufficiency from any cause. However, MV can be injurious to the lungs, particularly when high tidal pressures or volumes are used in the management of Acute Respiratory Distress Syndrome (ARDS) or similar acute lung injuries. The hallmark of ARDS is extensive alveolar collapse resulting in hypoxemia and carbon dioxide retention. Application of Positive End Expiratory Pressure (PEEP) is used to prevent derecruitment of alveolar units. Hence, there is a delicate trade-off between applied pressure and volume and benefit of lung recruitment. Current clinical practice lacks a practical method to easily determine the patient specific condition at the bedside without excessive extra tests and intervention. Hence, individual patient treatment is primarily a mixture of "one size- fits-all" protocols and/or the clinician's intuition and experience. A quasi-static, minimal model of lung mechanics is developed based on fundamental lung physiology and mechanics. The model consists of different components that represent a particular mechanism of the lung physiology, and the total lung mechanics are derived by combining them in a physiologically relevant and logical manner. Three system models are developed with varying levels of physiological detail and clinical practicality. The final system model is designed to be directly relevant in current ICU practice using readily available non-invasive data. The model is validated against a physiologically accurate mechanical simulator and clinical data, with both approaches producing clinically significant results. Initial validation using mechanical simulator data showed the model's versatility and ability to capture all physiologically relevant mechanics. Validation using clinical data showed its practicality as a clinical tool, its robustness to noise and/or unmodelled mechanics, and its ability to capture patient specific responses to change in therapy. The model's capability as a predictive clinical tool was assessed with an average prediction error of less than 9% and well within clinical significance. Furthermore, the system model identified parameters that directly indicate and track patient condition, as well as their responsiveness to the treatment, which is a unique and potentially valuable clinical result. Full clinical validation is required, however the model shows significant potential to be fully adopted as a part of standard ventilator treatment in critical care.

We have studied gas flow and particle deposition in a realistic three-dimensional model of the bronchial tree, extending from the trachea to the segmental bronchi (7th airway generation for the most distal ones) using Computational Fluid Dynamics (CFD). The model is based on the morphometrical data of Horsfield et al. [J. Appl. Physiol., 31: 207-217, 1971] and on bronchoscopic and CT images, which give the spatial 3D-orientation of the curved ducts. It incorporates realistic angles of successive branching planes. Steady inspiratory flow varying between 50cm³/s and 500cm³/s was simulated as well as deposition of spherical aerosol particles (1 to 7 m diameter, 1g/cm³ density). Flow simulations indicated non-fully developed flows in the branches because of their relative short lengths. Velocity flow profiles in the segmental bronchi, taken one diameter downstream the bifurcation, were distorted compared with the flow in a simple curved tube, and wide patterns of secondary flow fields were observed. Both were due to the asymmetrical 3D configuration of the bifurcating network. Viscous pressure drop in the model was compared with results obtained by Pedley et al. [Respir Physiol, 9: 387-405, 1970], which are shown to be a good first approximation. Particle deposition increased with particle size and was minimal for approximately 200cm³/s inspiratory flow but it was highly heterogeneous for branches of the same generation.

L’étude engagée dans cette thèse consiste à mettre en place une modélisation numérique fiable et complète du transport et du dépôt des particules dans un écoulement pulmonaire en se basant sur l’utilisation du code de calcul commercial CFD-ACE. Ce code intègre un solveur fluide qui résout les équations de Navier-Stokes incompressibles dans une formulation volumes finis. Le logiciel CFD-GEOM a été utilisé pour créer les surfaces en 3D de la géométrie générique du modèle de Weibel et ainsi générer le maillage non-structuré tétraèdrique en volumes finis. Dans le cadre de ce travail, il est supposé que le flux d’air est laminaire, stationnaire (ou instationnaire uniquement dans les modèles bronchiques) et incompressible ; les particules de diamètre 5μm sont sphériques et sans interaction. Le pourcentage global et local du dépôt des particules dans les poumons peut s’exprimer comme une efficacité de dépôt et se définit par le rapport entre le nombre de particules déposées dans une région donnée et le nombre total de particules admises initialement à l’entrée de la conduite. L’efficacité de dépôt dépend fortement du nombre de Stokes d’entrée, des conditions d’admission en termes de profil de vitesse du fluide (nombre de Reynolds d’entrée), de la distribution et des caractéristiques des particules. Nous avons donc modélisé avec succès les écoulements ainsi que le transport et le dépôt de particules dans des configurations simples (modèles de Weibel) et des configurations réalistes (poumons de rat et du lapin) et ce que l’on en peut dire c’est que la simulation, bien que coûteuse (surtout pour le dépôt des particules), ne présente pas de difficultés insurmontables. Par contre l’obtention d’une géométrie réaliste et la génération du maillage associé reste une étape délicate. / The study undertaken in this thesis is to develop a reliable and comprehensive numerical modeling of transport and deposition of particles in pulmonary flow based on the use of CFDACE computer code. This code includes a fluid solver that solves the Navier-Stokes in a finite volume formulation. The CFD-GEOM software was used to create 3D surfaces of the geometry of the generic model of Weibel and generate the unstructured tetrahedral finite volume mesh. As part of this work, it is assumed that the airflow is laminar, steady (unsteady only in bronchial models) ; the particles of diameter 5μm are spherical and noninteracting. The percentage of global and local particle deposition in the lungs can be expressed as a deposition efficiency and is defined as the ratio between the number of particles deposited in a given area and the total number of particles initially admitted to the entrance of lungs. The deposition efficiency depends strongly on the Stokes number of entry, the airflow fluid velocity profile (Reynolds number at the inlet), the distribution and characteristics of particles. We have successfully modeled the flow, the transport and deposition of particles in simple configurations (models of Weibel), realistic configurations (lungs of rats and rabbits) and we can conclude that the simulation, al though expensive in terms of computer memory & time (especially for particle deposition), does not present insurmountable difficulties. On the other hand, obtaining a realistic geometry and mesh generation main a challenge.

The administration of pharmaceutical aerosols to infants on mechanical ventilation needs to be improved by increasing the efficiency of delivery devices and creating better ways of evaluating potential therapies. Aerosolized medicines such as surfactants have been administered to ventilated infants with mixed results, but studies have shown improvement in respiratory function with a much lower dose than with liquid instillation through an endotracheal tube (ETT). An aerosolized medicine must be transported through the ventilation tubing and deposit in the lungs to have the desired therapeutic response. This work has taken a systematic approach to (i) develop new devices for the efficient production of small sized charged pharmaceutical aerosols, (ii) adapt a lead device to an infant ventilation system, (iii) develop a novel breathing infant lung (BIL) in vitro model capable of capturing lung delivery efficiency in an infant without the need for human subjects testing, and (iv) evaluate the hypothesis that small sized charged pharmaceutical aerosols can improve drug delivery efficiency to the lungs of a ventilated infant. Three new devices were developed and screened for the efficient generation of small sized charged pharmaceutical aerosols, which were: wick electrospray, condensational vapor, and a modified vibrating mesh nebulizer in a streamlined low flow induction charger (LF-IC). Of these devices, only the LF-IC produced a small [mean(SD) = 1.6(0.1) micrometers] and charged (1/100 Rayleigh limit) aerosol at a pharmaceutically relevant production rate [mean(SD) = 183(9) micrograms per minute]. The LF-IC was selected as a lead device and adapted for use in an infant ventilation system, which produced an increase in in vitro lung filter deposition efficiency from 1.3% with the commercial system to 34% under cyclic ventilation conditions. The BIL model was first shown to produce a realistic pressure-volume response curve when exposed to mechanical ventilation. The optimized LF-IC was then implemented in the BIL model to demonstrate superior reduction in inspiratory resistance when surfactant was delivered as an aerosol compared to liquid instillation. For the delivery of an aerosolized medication, the lung deposition efficiency increased from a mean(SD) 0.4(0.1)% when using the conventional delivery system to 21.3(2.4)% using the LF-IC in the BIL model, a 59-fold increase. The charged aerosol produced by the LF-IC was shown to have more depositional loss in the LF-IC than an uncharged aerosol, but the charge decreased the exhaled fraction of aerosol by 17%, which needs additional study to achieve statistical significance. Completion of this work has produced a device that can achieve lung delivery efficiency that is 59-fold greater than aerosols from conventional vibrating mesh nebulizers in invasively ventilated infants using a combination of small particle size, synchronization with inspiration and appropriate charge. The BIL model produced in this work can be used to test clinically relevant methods of administering medications to infants and can be used to provide more accurate delivery estimates for development of new nebulizers and inhalers. The LF-IC developed in this work could be used for controlled and efficient delivery of aerosolized antibiotics, steroids, non-steroidal anti-inflammatories, surfactants, and vasodilators.

Le thème des travaux qui fait l'objet de ce mémoire de thèse s'inscrit dans le cadre de la caractérisation de systèmes biologiques par modèles non entiers. Cette thèse comporte deux parties qui reposent sur deux collaborations distinctes. La première s'appuie sur une collaboration avec le laboratoire Mouvement Adaptation Cognition de l'Université Bordeaux 2 et l'institut Magendie de l'Inserm. L'objectif de ce travail consiste à étudier l'influence la longueur du muscle sur sa dynamique dans les cas de variations statiques et dynamiques de cette grandeur. La deuxième collaboration est un projet original, en partenariat avec l'équipe Anesthésiologie-Réanimation II du CHU Haut-Lévêque ayant pour but l'identification de transfert thermique dans le poumon au cours d'opération à cœur ouvert, grâce à des mesures obtenues sur des poumons de mouton. / This PhD thesis deals with biological system characterization using fractional models. This study is divided in two parts stemming from two different cooperations. The first one involves the laboratoire Mouvement Adaption Cognition of Université Bordeaux 2 and the Institut Magendie of Inserm. The aim of this teamwork is to study the muscle length effect on its dynamic, considering static and dynamical length variations. The second collaboration involves the Anesthésiologie-Réanimation team of CHU Haut-Lévêque from Bordeaux. This research work aims at identifying models of thermal transfer inside the lungs during open-heart surgery.

We have studied gas flow and particle deposition in a realistic three-dimensional model of the bronchial tree, extending from the trachea to the segmental bronchi (7th airway generation for the most distal ones) using Computational Fluid Dynamics (CFD). The model is based on the morphometrical data of Horsfield et al. [J. Appl. Physiol. 31: 207-217, 1971] and on bronchoscopic and CT images, which give the spatial 3D-orientation of the curved ducts. It incorporates realistic angles of successive branching planes. Steady inspiratory flow varying between 50cm³/s and 500cm³/s was simulated as well as deposition of spherical aerosol particles (1 to 7& / Doctorat en sciences appliquées / info:eu-repo/semantics/nonPublished

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