Thesis (M.Sc.)--University of Adelaide, Dept. of Human Physiology and Pharmacology, 1973.

No description available.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Anesthesiology. Bibliography: leaves 103-118. Also available online via the Internet.

Thesis (Ph.D.)--Virginia Commonwealth University, 2008. / Prepared for: Dept. of Anesthesiology. Title from title-page of electronic thesis. Bibliography: leaves 103-118.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1981. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 332-348).

Thesis (M.E. 1975) from the Department of Electrical Engineering, University of Adelaide.

Decompression sickness (DCS) results from a sudden decrease in ambient pressure leading to super-saturation of tissues with inert gas and subsequent bubble formation within both tissues and blood. Perfluorocarbons (PFC) are able to dissolve vast amounts of non-polar gases. The administration of intravenous (I.V.) PFC emulsions reduce both morbidity and mortality of DCS, but the mechanism of this protective effect has not yet been demonstrated. Juvenile Dorper cross sheep between 16 and 24 kg (n=31) were anaesthetized and instrumented for physiological monitoring, the administration of I.V. fluids and sampling of arterial and mixed venous blood. Animals were placed in a hyperbaric chamber and compressed to 6.0 atmospheres absolute for 30 minutes, then rapidly decompressed. Upon chamber exit animals were randomly assigned to receive 6cc/kg of either PFC or saline control over 5 minutes beginning immediately after chamber exit. They were also randomized to receive one of 4 breathing gases post-chamber: 100% O2, 80/20 N2/O2, 50/50 HeO2, or 80/20 HeO2. Blood samples were drawn at 5, 10, 15, 30, 60, and 90 minutes to examine whole-body oxygenation. Respiratory gases were monitored and recorded in real-time using mass spectroscopy to examine nitrogen washout. PFC administration increased arterial oxygen content (16.30±0.27 vs. 14.75±0.25 mL/dL, p<0.0001), oxygen delivery (14.83±0.28 vs. 13.44±0.25 mL/minute/kg, p=0.0004), and tissue oxygen consumption (3.37±0.14 vs. 2.76±0.13 mL/minute/kg, p=0.0018) over saline control, but did not increase mixed venous oxygen content (12.45±0.26 vs. 11.74±0.24 mL/dL, p=0.0558) or extraction ratio (0.23±0.012 vs. 0.21±0.011, p=0.1869). PFC administration lowered the plateau of the curve, increasing the amount of nitrogen washout vs. saline control (22.22±1.566 vs. 15.98±1.380 mmHg, p= 0.0074). Breathing 80/20 HeO2 increased the decay constant of the curve, increasing the rate of washout vs. breathing 100% O2 (0.03176±0.001044 vs. 0.03096±0.0009402, p=0.5777). PFC improves whole-body oxygenation after severe DCS and increases the amount of nitrogen washout. Although the effects of both PFC and 80/20 HeO2 breathing were statistically significant the magnitude of the nitrogen washout effect is quite small, and unlikely to be clinically significant. Thus it is likely that the improved oxygenation is responsible for the previously-observed therapeutic effects of PFC in treating DCS.

<p>The work presented in this dissertation is focused on applying engineering methods to develop and explore probabilistic survival models for the prediction of decompression sickness in US NAVY divers. Mathematical modeling, computational model development, and numerical optimization techniques were employed to formulate and evaluate the predictive quality of models fitted to empirical data. In Chapters 1 and 2 we present general background information relevant to the development of probabilistic models applied to predicting the incidence of decompression sickness. The remainder of the dissertation introduces techniques developed in an effort to improve the predictive quality of probabilistic decompression models and to reduce the difficulty of model parameter optimization.</p><p>The first project explored seventeen variations of the hazard function using a well-perfused parallel compartment model. Models were parametrically optimized using the maximum likelihood technique. Model performance was evaluated using both classical statistical methods and model selection techniques based on information theory. Optimized model parameters were overall similar to those of previously published Results indicated that a novel hazard function definition that included both ambient pressure scaling and individually fitted compartment exponent scaling terms. </p><p>We developed ten pharmacokinetic compartmental models that included explicit delay mechanics to determine if predictive quality could be improved through the inclusion of material transfer lags. A fitted discrete delay parameter augmented the inflow to the compartment systems from the environment. Based on the observation that symptoms are often reported after risk accumulation begins for many of our models, we hypothesized that the inclusion of delays might improve correlation between the model predictions and observed data. Model selection techniques identified two models as having the best overall performance, but comparison to the best performing model without delay and model selection using our best identified no delay pharmacokinetic model both indicated that the delay mechanism was not statistically justified and did not substantially improve model predictions.</p><p>Our final investigation explored parameter bounding techniques to identify parameter regions for which statistical model failure will not occur. When a model predicts a no probability of a diver experiencing decompression sickness for an exposure that is known to produce symptoms, statistical model failure occurs. Using a metric related to the instantaneous risk, we successfully identify regions where model failure will not occur and identify the boundaries of the region using a root bounding technique. Several models are used to demonstrate the techniques, which may be employed to reduce the difficulty of model optimization for future investigations.</p> / Dissertation

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

Si le phénomène bullaire reste le primum movens à l’origine de l’obstruction vasculaire lors de la décompression, les plaquettes sanguines jouent un rôle déterminant dans la physiopathologie de l’accident de décompression (ADD). L’objectif de ces travaux était d’étudier les mécanismes à l’origine de cette agrégation plaquettaire induit par le phénomène bullaire. La première étape a permis de valider un modèle animal d’ADD chez le rat et de confirmer que le degré d’agrégation constituait un indice fiable de sévérité de l’ADD. La seconde a eu pour but d’étudier différents marqueurs spécifiques de l’activation plaquettaire. La troisième étape a étudié les effets de différents anti-agrégants plaquettaires administrés avant l’exposition. Les résultats confirment que le clopidogrel, un inhibiteur spécifique des récepteurs à l’ADP, a un effet protecteur sur le risque de survenue et la sévérité des ADD en réduisant l’importance de l’agrégation plaquettaire. Ces résultats sont en faveur d’un mécanisme d’agrégation ADP-dépendant conséquence des interactions entre les plaquettes et les bulles circulantes. La génération de thrombine, un autre puissant agoniste plaquettaire, interviendrait dans la genèse d’un état pro-thrombotique loco-régional conséquence des lésions induites par le passage des bulles au contact de l’endothélium vasculaire. Enfin, les résultats montrent le rôle joué par les micro-particules dans la diffusion à distance de cet état pro-thrombotique. Des études à venir devront confirmer l’intérêt d’une utilisation du clopidogrel dans le traitement de l’ADD ainsi que le rôle de l’oxyde nitric, de la prostacycline PGI2 et du shear-stress dans l’effet protecteur des vibrations et de l’exercice physique sur le risque de survenue de l’ADD en réduisant l’agrégation plaquettaire et en optimisant la cinétique d’élimination des bulles circulantes. / If bubble-induced mechanical obstruction of vessels is the central event during decompression, blood platelets play a key role in the pathogenesis of decompression sickness (DCS). But bubble-induced platelet aggregation (BIPA) mechanisms are unknown. In a previous study, we highlighted a post-dive decrease in platelet count in divers. The aims of this study was therefore to validate an experimental model of DCD in rat to clarify relationship between blood platelet and bubble formation, investigate platelet activation by measuring different platelet markers, and to study the effects of different antithrombotic pre-treatments. First, the results clearly indicate that clopidogrel, a powerful ADP-inhibitor, has a protective effect on decompression risk improving significantly DCS outcome and reducing DCS severity. The results point to the predominant involvement of the ADP release in the BIPA mechanism. Second, we showed the participation of thrombin generation, a powerful platelet agonist, in the thrombotic event. If local BIPA seems to be the direct consequence of bubble-blood component interactions in vascular bed, the regional thrombotic event could be the consequence of bubble-induced vessel wall injury with a key role played by micro-particles in the general extend. Further human studies should be aimed at demonstrating that clopidogrel can offer a benefit as an adjuvant in DCS treatment and the role played by nitric oxyd and prostacyclin in the protective effect of vibrations and physical exercise on DCS risk reducing bubble-induced platelet aggregation