The lymphatic system consists of a network of vessels which work to return the interstitial fluid back to the blood circulation. Individual units called lymphangions, segments of lymphatic vessels between two valves, pump cyclically to propel lymph. Lymphangions are similar to the heart in that they are sensitive to both preload and afterload. To describe the heart independent of preload and afterload, investigators developed the concept of time-varying elastance. We evaluated the applicability of this concept to lymphangions by analyzing preliminary data obtained from the bovine mesenteric vessels. We found that there were some limitations to the applicability of this concept to lymphangions, as there was a high degree of variability with respect to contraction strength and frequency of individual time-varying elastance curves. To better characterize lymphangion mechanics, we built a device which would enable real-time isobaric, isometric and isotonic experiments in vitro. We performed all three experiments on lymphatic vessel segments and obtained input and output pressures, output flow, instantaneous radii and wall tension. The characterization of the lymphangion using these parameters can be the first step to simulate the behavior of a lymphatic vesssel and later the behavior of an entire lymphatic system.

The intensive care unit treats the most critically ill patients in the hospital, and as such the clinical staff in the intensive care unit have to deal with complex, time-sensitive and life-critical situations. Commonly, patients present with multiple organ dysfunctions, require breathing and cardiovascular support, which make diagnosis and treatment even more challenging. As a result, clinical staff are faced with processing large quantities of often confusing information, and have to rely on experience and trial and error. This occurs despite the wealth of cardiovascular metrics that are available to the clinician. Computer models of the cardiovascular system can help enormously in an intensive care setting, as they can take the monitored data, and aggregate it in such a way as to present a clear and understandable picture of the cardiovascular system. With additional help that such systems can provide, diagnosis can be more accurate and arrived at faster, alone with better optimised treatment that can start sooner, all of which results in decreased mortality, length of stay and cost. This thesis presents a model of the cardiovascular system, which mimics a specific patient’s cardiovascular state, based on only metrics that are commonly measured in an intensive care setting. This intentional limitation gives rise to additional complexities and challenges in identifying the model, but do not stand in the way of achieving a model that can represent and track all the important cardiovascular dynamics of a specific patient. One important complication that comes from limiting the data set is need for an estimation for the ventricular time-varying elastance waveform. This waveform is central to the dynamics of the cardiovascular model and is far too invasive to measure in an intensive care setting. This thesis thus goes on to present a method in which the value-normalised ventricular time-varying elastance is estimated from only metrics which are commonly available in an intensive care setting. Both the left and the right ventricular time-varying elastance are estimated with good accuracy, capturing both the shape and timing through the progress of pulmonary embolism and septic shock. For pulmonary embolism, with the algorithm built from septic shock data, a time-varying elastance waveform with median error of 1.26% and 2.52% results for the left and right ventricles respectively. For septic shock, with the algorithm built from pulmonary embolism data, a time-varying elastance waveform with median error of 2.54% and 2.90% results for the left and right ventricles respectively. These results give confidence that the method will generalise to a wider set of cardiovascular dysfunctions. Furthermore, once the ventricular time-varying elastance is known, or estimated to a adequate degree of accuracy, the time-varying elastance can be used in its own right to access valuable information about the state of the cardiovascular system. Due to the centrality and energetic nature of the time-varying elastance waveform, much of the state of the cardiovascular system can be found within the waveform itself. In this manner this thesis presents three important metrics which can help a clinician distinguish between, and track the progress of, the cardiovascular dysfunctions of pulmonary embolism and septic shock, from estimations based of the monitored pressure waveforms. With these three metrics, a clinician can increase or decrease their probabilistic measure of pulmonary embolism and septic shock.

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Systemic cardiovascular effects of volatile and intravenous anesthetics :evaluation in the time domain, the frequency domain and the pressure-volume plane.<p>Cardiovascular stability is of prime importance in order to maintain homeostasis during anesthesia and intensive care, and to reduce cardiovascular perioperative morbidity and mortality.<p>General anesthesia does have profound cardiovascular effects, and the end result is usually a decrease in arterial pressure, with the potential of inadequate organ perfusion and consequently organ damage. Therefore, elucidation of the mechanisms of cardiovascular effects of general anesthesia is important in order to prevent and/or to treat adequately the cardiovascular perturbations, and to perform the optimal choice of the anesthetic management. Anesthetic management for the patient presenting with cardiovascular alterations relates essentially to the question of a volatile anesthetic based regimen versus a propofol based anesthetic regimen.<p>A traditional hemodynamic investigation includes the measurement of heart rate, systemic and pulmonary arterial pressure, the filling pressures of the heart and cardiac output. These measurements allows for the calculation of systemic vascular resistance in order to evaluate arterial tone. However, calculated systemic vascular resistance cannot discriminate between passive (flow-dependent) and active (tone-dependent) changes in arterial pressure. Changes in arterial tone must be assessed by constructing pressure-flow plots.<p>Neither calculated systemic vascular resistance nor pressure-flow plots takes into account the pulsatile nature of the circulation. In order to do so, one has to measure instantaneous pressure and flow waves, perform harmonic analysis on both waves and calculate vascular impedance spectra.<p>The cardiovascular system is a mechanical system in which two components are functionally coupled: there is an energy transfer between the energy source, i.e. the left ventricle, and its mechanical load, i.e. the arterial tree. An alteration in one of these components necessitates an appropriate alteration in the other component in order to maintain optimal coupling, i.e. maximal energy transfer between the two elements. In the pressure-volume plane the left ventricle and the arterial tree are considered to be two elastic chambers in series. The performance of the left ventricle is quantified by the end-systolic elastance, while the load of the arterial tree is quantified by the effective arterial elastance. The ratio of end-systolic elastance to effective arterial elastance relates ventricular-arterial coupling to either maximisation of stroke work or either to maximisation of mechanical efficiency (i.e. the ratio of mechanical power output to cardiac oxygen consumption).<p>In the first experiment we investigated the systemic vascular effects of isoflurane versus propofol anesthesia in dogs using a traditional hemodymamic approach, measurement of instantaneous aortic flow and pressure with subsequent calculation of aortic input impedance spectra, and construction of pressure-flow plots generated by gradual reduction of venous return. Calculated systemic vascular resistance could not detect differences in arteriolar tone between isoflurane and propofol, whereas pressure-flow plots did: compared with isoflurane, propofol better maintained aortic pressure at all levels of flow, except at the lowest level of flow. Impedance spectra demonstrated a decreased pulsatile load and less energy losses in pulsations with propofol as compared with isoflurane.<p>In the second experiment we investigated the effects of escalating doses of sevoflurane and propofol anesthesia on arterial mechanical properties and left ventricular-arterial coupling in the dog. Arterial mechanics were assessed by traditional hemodynamics, aortic input impedance spectra, and pressure-flow plots generated by rapid caval inflow reduction. Left ventricular-arterial coupling was assessed as the ratio of end-systolic elastance to effective arterial elastance. The end-systolic elastance and the effective arterial elastance were obtained from left ventricular pressure and aortic flow data using a ‘single-beat’ estimation method. Traditional hemodynamics and pressure-flow plots demonstrated that sevoflurane causes a limited arteriolar vasodilation and causes arterial hypotension essentially by a decrease of cardiac output. Propofol insignificantly decreases cardiac output, but is an “actual” arteriolar dilator. The impedance spectra demonstrated that sevoflurane and propofol do have different effects on the elastic properties of large conduit arteries. Sevoflurane increased the characteristic impedance and reduced arterial compliance, indicating an increased physical elastance of the arterial tree. Propofol caused an insignificant increase of the characteristic impedance and the arterial compliance remained unaltered, suggesting that propofol does have a beneficial effect on the elastic properties of the arterial tree, thereby confirming the conclusion of the first experiment (i.e. a decreased pulsatile load with propofol). Sevoflurane impaired ventricular-arterial coupling by decreasing end-systolic elastance and increasing effective arterial elastance. Propofol maintained left ventricular-arterial coupling: the end-systolic elastance and effective arterial elastance remained unchanged and as consequence the ratio of end-systolic elastance to effective arterial elastance did not change. All results taken together we conclude that sevoflurane decreases cardiac output and left ventricular contractility, and increases the pulsatile and total load to the left ventricle. Propofol maintains cardiac output and left ventricular contractility, induces an arterial dilatation but without affecting the pulsatile and total load to the left ventricle.<p>These results, obtained in dogs, suggest that propofol, compared to volatile anesthetics, is an anesthetic, which can better preserve hemodynamic stability and homeostasis in the cardiovascular compromized patient undergoing surgery.<p>/<p>Evaluation des effets cardiovasculaires systémiques des agents anesthésiques dans le domaine du temps, le domaine de la fréquence et le plan pression-volume.<p>La stabilité cardiovasculaire est d’une importance prioritaire pour maintenir l’homéostasie pendant l’anesthésie et le séjour aux soins intensifs, et pour réduire la morbidité et mortalité cardiovasculaire pendant la période péri-opératoire.<p>L’anesthésie générale exerce des effets marqués sur le système cardiovasculaire. Généralement une hypotension artérielle systémique est observée, avec la possibilité d’une hypoperfusion des organes vitaux et ultérieurement des lésions de ces mêmes organes. Donc l’éclaircissement des mécanismes des effets cardiovasculaires de l’anesthésie générale est important pour prévenir et traiter les perturbations cardiovasculaires, et pour effectuer le choix optimal de la gestion anesthésique.<p>La question de la gestion anesthésique chez le patient présentant une fonction cardiovasculaire altérée se traduit essentiellement par le choix de l’anesthésie soit basée sur un agent volatile soit basée sur le propofol intraveineux.<p>Une exploration traditionnelle de l’hémodynamique comprend le mesure de la fréquence cardiaque, des pressions artérielles systémique et pulmonaire, des pressions de remplissage et du débit cardiaque. Ces mesures permettent de calculer la résistance vasculaire systémique de manière à évaluer le tonus artériel. Cela dit, la résistance vasculaire systémique calculée ne peut pas faire la différence entre des changements actifs (changements du tonus artériel) ou passifs (changements des débits) de la pression artérielle systémique. Les changements du tonus artériel doivent être évalués par des courbes pression - débit.<p>Ni les résistances vasculaires systémiques ni les courbes pression débit ne tiennent compte de la nature pulsatile de la circulation. L’exploration des effets pulsatiles<p>requiert tout d’abord la mesure des pressions instantanées et des débits instantanés. En seconde lieu, ces signaux doivent subir une décomposition harmonique (analyse de Fourier), pour afin de pouvoir calculer le spectre d’impédance vasculaire.<p>Le ventricule gauche et le système artériel sont deux éléments d’un système mécanique, dans lesquels il y a un transfert d’énergie entre la source d’énergie et sa charge. Une modification dans un des éléments nécessite une modification appropriée dans l’autre élément pour maintenir un couplage optimal entre les deux éléments, c'est-à-dire un transfert maximal d’énergie. Dans le plan pression volume, le ventricule gauche et l’arbre artériel sont considérés comme deux chambres élastiques en série.<p>La performance du ventricule gauche est quantifiée par l’élastance ventriculaire télésystolique, et la charge du système artériel est quantifiée par l’élastance artérielle effective. Le rapport entre l’élastance ventriculaire télésystolique et l’élastance artérielle effective permet de situer le « couplage ventriculo-artériel » soit en termes de maximisation du travail ventriculaire ou soit en termes d’ efficience mécanique. L’efficience myocardique est définie comme un rapport entre la puissance ventriculaire produite et l’oxygène consommé.<p>Dans la première expérimentation, nous avons étudié les effets vasculaires sur la circulation systémique du chien d’une anesthésie inhalatoire à l’isoflurane versus une anesthésie au propofol, ceci au moyen d’une exploration hémodynamique traditionnelle, les spectres d’impédance aortique et les courbes pression débit étant générées par une réduction graduelle du retour veineux. Les résistances vasculaires systémiques calculées n’ont pas décelé de différences de tonus artériolaire entre les effets d’une anesthésie inhalatoire à l’isoflurane et les effets d’une anesthésie intraveineuse au propofol. Par contre les courbes pression-débit démontrent une différence :comparé à l’anesthésie à l’isoflurane, l’anesthésie au propofol maintientt mieux la pression aortique à tous les niveaux de débit sanguin sauf aux débits les plus bas. Les spectres d’impédance démontrent une charge pulsatile réduite et des pertes d’énergie réduites avec le propofol par rapport à l’isoflurane.<p>Dans la seconde expérimentation chez le chien, nous avons étudié les effets de doses croissantes de deux agents anesthésiques généraux, le sevoflurane et le propofol, sur les caractéristiques mécaniques du système artériel et le couplage ventriculo- artériel systémique. La mécanique artérielle était étudiée par une exploration hémodynamique traditionnelle, les spectres d’impédance aortique et les courbes pression-débit étant générées par une réduction rapide du retour veineux. Le couplage ventriculo-artériel systémique était calculé par le rapport entre l’élastance ventriculaire télésystolique et l’élastance artérielle effective. L’élastance ventriculaire télésystolique et l’élastance artérielle effective ont été estimées à partir de la pression ventriculaire gauche et du débit aortique instantané en appliquant une méthode dite de « single beat ». L’hémodynamique traditionnelle et les courbes pression - débit démontrent que le sevoflurane provoque une vasodilatation artériolaire limitée et que la cause principale de l’hypotension artérielle est une réduction du débit cardiaque. Le propofol réduit le débit cardiaque d’une manière non significative, mais est un vasodilatateur artériolaire réel. Les spectres d’impédance montrent que le sevoflurane et le propofol ont des effets différents sur les caractéristiques élastiques des grosses artères à conduction. Le sevoflurane augmente l’impédance caractéristique et réduit la compliance artérielle, indiquant une augmentation de l’élastance physique de l’arbre artériel. Le propofol provoque une augmentation non significative de l’impédance caractéristique, mais la compliance artérielle reste inchangée. Ces résultats suggèrent que le propofol aurait un effet favorable sur les propriétés élastiques de l’arbre artériel, et donc confirment les conclusions de la première expérimentation, c’est-à-dire une charge pulsatile réduite avec le propofol. Le sevoflurane dégrade le couplage ventriculo-artériel à la suite d’une réduction de l’élastance ventriculaire télésystolique et d’une augmentation de l’élastance artérielle effective. Le propofol maintient le couplage ventriculo-artériel. L’élastance ventriculaire télésystolique et l’élastance artérielle effective restent par contre inchangées. Par conséquent, le rapport entre les deux élastances ne change pas. Sur base de ces résultats, nous concluons que le sevoflurane réduit le débit cardiaque et la contractilité du ventricule gauche, et augmente la charge pulsatile et totale sur le ventricule gauche. Le propofol maintient le débit cardiaque et la contractilité du ventricule gauche, et induit une dilatation artérielle sans altérer la charge pulsatile et totale sur le ventricule gauche.<p>Ces résultats, obtenus chez le chien, suggèrent que le propofol, comparé aux anesthésiques volatiles, est un anesthésique qui permet de mieux préserver la stabilité hémodynamique et l’homéostasie chez le patient présentant une fonction cardiovasculaire restreinte et devant bénéficier d’un acte chirurgical.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.