This thesis is concerned with the chemical control of breathing during exercise in humans. Chapter 1 reviews some of the relevant studies in animals and humans. Chapter 2 describes the experimental apparatus and the technique of dynamic end-tidal forcing performed using a computer-controlled gas-mixing system. Chapter 3 describes a study of the effects of sustained hypoxia on ventilation during steady exercise. The acute ventilatory response to hypoxia (AHR) was increased during exercise as compared with rest, but the magnitude of the subsequent decline in ventilation (HVD), expressed as a fraction of the AHR, was reduced. A simple model of the hypoxic peripheral chemoreflex is proposed, in which the mechanisms underlying AHR and HVD are functionally separate and can be independently modulated by external factors. Chapter 4 assesses changes in peripheral chemoreflex sensitivity to hypoxia in terms of the degree of decline in AHR measured in the resting periods shortly after prior conditioning periods of hypoxia and/or exercise. At rest, a second AHR measured 6 min after a period of sustained hypoxia had declined by 30% as compared with the initial AHR. In contrast, the AHR measured in the resting period after a period of sustained hypoxic exercise was only 11% smaller in magnitude than the AHR measured after a period of euoxic exercise. The results suggest that the degree to which hypoxic sensitivity declines during sustained hypoxia is genuinely attenuated, rather than masked, by exercise. Chapter 5 describes the changes in respiration during prolonged exercise breathing air with and without added CO₂. During prolonged poikilocapnic exercise, ventilation remained constant, but metabolic CO₂ production, respiratory quotient and end-tidal P_CO2 declined; a result which suggests that in man, ventilation can be dissociated from the CO₂ flux. During hypercapnic exercise, ventilation progressively increased; this was interpreted as being due to a correction by end-tidal forcing of the natural tendency for end-tidal CO₂ to decline, together with an independent effect of CO₂ per se on the ventilation. Chapter 6. Electrical muscle stimulation was used as means of inducing non-volitional exercise. Electrically-induced exercise increased the AHR as compared with rest, and with voluntary exercise at matched external work rate. The AHRs during electrical stimulation and voluntary exercise matched to the internal work rate were similar. Chapter 7. Electrical muscle stimulation was used in paraplegic subjects in whom there would be no neural control of exercise. Electrically-induced exercise increased the AHR as compared with rest. When compared with the data from Chapter 6, the results suggest that the observed increase in AHR during normal voluntary exercise can be wholly accounted for by the increase in metabolic CO₂ production, or closely related factors. Chapter 8 presents a brief summary of the findings in this thesis.

Typewritten copy / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1954

The lungs are the primary organ of the respiratory system. Their main function is to provide freshly breathed oxygen (O²) to the blood capillaries, while taking carbon dioxide (CO²) from them and expelling it to the atmosphere. Lung conditions such as Acute Respiratory Distress Syndrome (ARDS), Idiopathic Pulmonary Fibrosis (IPF), Coronavirus Disease (COVID-19), etc., cause impaired gas exchange that is life-threatening. In this dissertation, I developed 1) a physiology-based dynamic pulmonary system to study the lung normo- and patho-physiology, and 2) a model-based constrained optimization algorithm to do parameter estimation in order to non-invasively assess lung health. The goals of this work are 1) to accomplish a respiratory personalized medicine example for clinical decision support, and 2) to further the understanding of respiratory physiology, via a mechanistic physiology-based model and system identification techniques. The mechanistic model presented in this thesis comprises six subsystems: 1) a lung mechanics module that computes airflow transport from the mouth and nose to the alveoli (gas exchange units), 2) a respiratory muscles and rib cage mechanics module that simulates the effect of the respiratory muscle contraction on the lungs and the rib cage, 3) a microvascular exchange system that describes fluid (water) and mass (albumin and globulin) transport between the pulmonary capillaries and the alveolar space, 4) an alveolar elasticity module that computes alveolar compliance as a function of the pulmonary surfactant concentration and the elastic properties of the lung tissue fiber, 5) a pulmonary blood circulation that describes blood transport from the heart to the pulmonary system, and 6) a gas exchange system that describes O² and CO² transport between blood in the pulmonary capillaries and gas in the alveoli. Each subsystem was developed based on the latest knowledge of lung physiology and was validated using patient data when available or published and validated physiology-based models. To our knowledge, the combined six-module model would be the most rigorous and expansive lung dynamic model in the literature. This dynamic respiratory system can be used to describe human breathing under healthy and diseased conditions. The model can readily be used to test different what-if scenarios to find the optimal therapy for the patients. Further, I tailor the proposed lung model and adopt system identification techniques for noninvasive assessment of the lung mechanical properties (resistance and compliance) and the patient breathing effort. Pulmonary syndromes or diseases, such as ARDS and COPD (Chronic Obstructive Pulmonary Disease) evoke alterations in lung resistance and compliance. These two parameters reflect, by and large, the state of health and functionality of the respiratory system. Hence tracking these two parameters can lead to better disease diagnosis and easier monitoring of the respiratory disease progression. For spontaneously breathing patients on ventilatory support, the estimation of the lung parameters is challenging due to the added patient’s breathing effort. This dissertation presents a model-based nonlinear constrained optimization algorithm to estimate, breath-by-breath, the lung resistance, the lung compliance, as well as the patient breathing effort due to the respiratory muscle activity, using readily available non-invasive measurements (airway opening pressure and airflow).

The original work presented in this thesis investigates some of the mechanisms that may be responsible for the aetiology of altitude-related cough. Particular attention is paid to its relationship to the long recognised, but poorly understood, changes in lung volumes that occur on ascent to altitude. The literature relevant to this thesis is reviewed in Chapter 1.<p><p>Widespread reports have long existed of a debilitating cough affecting visitors to high altitude that can incapacitate the sufferer and, on occasions, be severe enough to cause rib fractures (22, 34, 35). The prevalence of cough at altitude has been estimated to be between 22 and 42% at between 4200 and 4900 m in the Everest region of Nepal (10, 29). Traditionally the cough was attributed to the inspiration of the cold, dry air characteristic of the high altitude environment (37) but no attempts were made to confirm this aetiology. In the first formal study of cough at high altitude, nocturnal cough frequency was found to increase with increasing altitude during a trek to Everest Base Camp (5300 m) and massively so in 3 climbers on whom recordings were made up to 7000 m on Everest (8). After 9 days at 5300 m the citric acid cough threshold, a measure of the sensitivity of the cough reflex arc, was significantly reduced compared with both sea level and arrival at 5300 m.<p><p>During Operation Everest II, a simulated climb of Mount Everest in a hypobaric chamber, the majority of the subjects were troubled above 7000 m by pain and dryness in the throat and an irritating cough despite the chamber being maintained at a relative humidity of between 72 and 82% and a temperature of 23ºC (18). This argued against the widely held view that altitude-related cough was due to the inspiration of cold, dry air. <p><p>In the next major hypobaric chamber study, Operation Everest III, nocturnal cough frequency and citric acid cough threshold were measured on the 8 subjects in the study. The chamber temperature was maintained between 18 and 24ºC and relative humidity between 30 and 60% (24). This work is presented in Chapter 2 and, demonstrated an increase in nocturnal cough frequency with increasing altitude which immediately returned to control values on descent to sea level. Citric acid cough threshold was reduced at 8000 m compared to both sea level and 5000 m values. Changes in citric acid cough threshold at lower altitudes may not have been detected because of the constraints on subject numbers in the chamber. The study still however demonstrated an increase in clinical cough and a reduction in the citric acid cough threshold at extreme altitude, despite controlled environmental conditions, and thus refuted the long held belief that altitude-related cough is solely due to the inspiration of cold, dry air. <p><p>If altitude-related cough is not simply due to the inspiration of cold, dry air, other possible aetiologies are:<p>•\ / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Le principal objectif de ce travail est l’étude de l’influence de la pesanteur sur la mécanique <p>respiratoire et le contrôle de la respiration, ainsi que sur les interactions cardio-respiratoires pendant les différents stades du sommeil. <p><p>Le chapitre introductif présente le contexte général et les objectifs de la thèse. Des sections abordant le sommeil, la respiration, et l’interaction cardio-respiratoire y sont présentées, résumant l’état actuel des connaissances sur les effets de la pesanteur sur chacun de ces systèmes. <p>Dans le deuxième chapitre, l’expérience “Sleep and Breathing in microgravity”, qui constitue la source des données à la base de ce travail, est présentée en détail. <p>L’étude des signaux de longue durée requiert avant tout de disposer d’outils performants <p>d’analyse des signaux. La première partie de la thèse présente en détail deux algorithmes :un <p>algorithme de détection automatique d’événements respiratoires (inspiration / expiration) <p>basé sur des réseaux neuronaux artificiels, et un algorithme de quantification de l’amplitude <p>et de la phase de l’arythmie sinusale pendant le sommeil, utilisant la méthode des ondelettes. <p>La validation de chaque algorithme est présentée, et leur performance évaluée. Cette partie <p>inclut aussi des courtes introductions théoriques aux réseaux de neurones artificiels ainsi <p>qu’aux méthodes d’analyse temps–fréquence (Fourier et ondelettes). <p>Une approche similaire à celle utilisée pour la détection automatique d’événements respiratoires a été appliquée à la détection d’événements dans des signaux de vitesse du sang <p>dans l’artère cérébrale moyenne, mesures obtenues par Doppler transcrânien. Ceci est le <p>sujet de la thèse annexe. <p>Ces deux algorithmes ont été appliqués aux données expérimentales pour extraire des <p>informations physiologiques quant à l’impact de la pesanteur sur la mécanique respiratoire et <p>l’interaction cardio-respiratoire. Ceci constitue la deuxième partie de la thèse. Un chapitre <p>est consacré aux effets de l’apesanteur sur la mécanique respiratoire pendant le sommeil. <p>Ce chapitre a mis en évidence, pour tous les stades de sommeil, une augmentation de la <p>contribution abdominale en microgravité, suivi d’un retour progressif vers des valeurs observées avant le vol. L’augmentation initiale était attendue, mais l’adaptation progressive <p>observée ne peut pas être expliquée par un effet purement mécanique, et nous suggère la <p>présence d’un mécanisme d’adaptation central. Un deuxième chapitre présente les résultats <p>comparant l’arythmie sinusale pendant le sommeil avant le vol, en apesanteur et après le retour sur terre. Le rythme cardiaque pendant le sommeil dans l’espace présente une moindre <p>variabilité. Les différences NREM–REM observées sur terre pour les influences vagales et sympathiques sont accentuées dans l’espace. Aucun changement significatif n’est présent pour <p>le gain et la différence de phase entre les les signaux cardiaque et respiratoire en comparant <p>le sommeil sur terre et en apesanteur. <p>La dissertation termine par une discussion générale du travail effectué, incluant les prin- <p>cipales conclusions ainsi que les perspectives qui en découlent. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Ce travail a été consacré à l’étude non invasive de la circulation pulmonaire normale par mise en œuvre de l’échocardiographie Doppler. <p>En intégrant les mesures obtenues dans une approche physiopathologique, et en exploitant les nouvelles possibilités d’échocardiographes portables, techniquement performants, nous avons analysé les effets d’un inhibiteur de la phosphodiestérase-5 et d’une prostacycline, pour tenter d’en identifier d’éventuels effets introtropes intrinsèques, nous avons exploré le concept de réserve vasculaire pulmonaire comme facteur limitant de l’aptitude aérobie et indice potentiel d’une atteinte vasculaire pulmonaire précoce, et obtenu des résultats préliminaires permettant d’identifier une hypertension artérielle pulmonaire (HTAP) latente. Nos principaux résultats peuvent être résumés comme suit :<p>1. Chez le sujet sain, en normoxie ou dans un modèle expérimental d’HTAP induite par l’inhalation d’un mélange gazeux hypoxique, le sildenafil per os ou l’epoprostenol par voie intraveineuse, à des doses utilisées en clinique pour le traitement de l’HTAP, améliorent les indices de la fonction ventriculaire droite en proportion de leurs effets vasodilatatoires pulmonaires, sans effets inotropes intrinsèques détectables.<p>2. La consommation d’oxygène maximale du sujet sain augmente en raison directe de son volume capillaire pulmonaire (calculé à partir de sa capacité de diffusion pour l’oxyde nitrique et le monoxyde de carbone) et en raison inverse de sa résistance vasculaire pulmonaire, non seulement en altitude, mais aussi au niveau de la mer. Ce résultat suggère qu’une plus grande réserve vasculaire pulmonaire est propice aux efforts aérobiques intenses, probablement par moindre postcharge ventriculaire droite.<p>3. Des mesures réalisées chez un petit nombre de sujets suggèrent que la distensibilité vasculaire pulmonaire, calculée à partir d’une relation débit-pression vasculaire pulmonaire, est typiquement réduite chez des porteurs asymptomatiques de la mutation BMPR2, qui est actuellement le facteur de risque le plus élevé connu de l’HTAP. La mutation BMPR2 pourrait aussi être associée à une réactivité vasculaire pulmonaire accrue à l’hypoxie. <p>Nos résultats suggèrent indirectement que l’échocardiographie Doppler, de repos ou de stress, pourrait être davantage développée dans la mise au point de patients à risque d’HTAP./<p><p>Novel advances in echocardiography offer the opportunity to reliably characterize pulmonary circulation in terms of pressure-flow relationship, and to better understand the coupling of right ventricular (RV) function with normal and abnormal pulmonary hemodynamics. Moreover, when combined with the measurement of pulmonary capillary blood volume, this renewed methodological approach may help to understand the concept of pulmonary vascular reserve as a limiting factor of exercise capacity and potential sensitive marker of early vascular disease.<p><p>In the present work we used a model of hypoxic pulmonary vasoconstriction to analyse the effects of two targeted therapies of pulmonary arterial hypertension (PAH) on the RV function. We showed that the beneficial effects of these drugs are mainly driven by a decrease in RV afterload and not an enhanced myocardial inotropic state. Whether this is transposable to abnormal RV-arterial coupling in PAH patients remains to be investigated.<p><p>Echocardiography may be useful to explore the pulmonary vascular reserve as an important limiting factor of exercise capacity. We showed that a higher pulmonary vascular reserve, defined by a decreased PVR and increased lung diffusing capacity, allows for an improved aerobic exercise capacity (as assessed by a higher peak oxygen consumption), at a lower ventilatory cost, at sea level and at high altitude. <p><p>Stress echocardiography may detect an abnormal pulmonary vasoreactivity. We showed that asymptomatic relatives of patients suffering from idiopathic pulmonary arterial hypertension, and who carry a bone morphogenetic protein receptor type 2 mutation (BMPR2) present with a decreased pulmonary vascular distensibility and an enhanced pulmonary vasoreactivity to hypoxia, which are identifiable by echocardiography examination. However, the predictive value of these findings is not known. <p><p>Thus echocardiography may represent, in experienced and dedicated hands, a noninvasive, safe, widely available, applicable at the bed-side as well as in extreme environment (e.g. high altitudes), less expensive alternative for the evaluation of the pulmonary circulation, either by the interrogation of pressure-flow relationship (stress echocardiography), by the investigation of the right ventricle global and regional function in relation to its afterload (standard and Tissue Doppler Imaging), or by a combined approach with the measurement of lung diffusing capacity (DLNO / DLCO) to assess the pulmonary vascular reserve.<p><p>The present data are encouraging for further development and implementation of echocardiography for the detection, but also the diagnosis and follow-up of patients with pulmonary hypertension.<p><p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished