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Doctor of Philosphy (PhD) / This thesis describes the work carried out during four treks, each over 10-11 days, from 1400m to 5000m in the Nepal Himalaya and further work performed during several two-night sojourns at the Barcroft Laboratory at 3800m on White Mountain in California, USA. Nineteen volunteers were studied during the treks in Nepal and seven volunteers were studied at White Mountain. All subjects were normal, healthy individuals who had not travelled to altitudes higher than 1000m in the previous twelve months. The aims of this research were to examine the effects on sleep, and the ventilatory patterns during sleep, of incremental increases in altitude by employing portable polysomnography to measure and record physiological signals. A further aim of this research was to examine the relationship between the ventilatory responses to hypoxia and hypercapnia, measured at sea level, and the development of periodic breathing during sleep at high altitude. In the final part of this thesis the possibility of preventing and treating Acute Mountain Sickness with non-invasive positive pressure ventilation while sleeping at high altitude was tested. Chapter 1 describes the background information on sleep, and breathing during sleep, at high altitudes. Most of these studies were performed in hypobaric chambers to simulate various high altitudes. One study measured sleep at high altitude after trekking, but there are no studies which systematically measure sleep and breathing throughout the whole trek. Breathing during sleep at high altitude and the physiological elements of the control of breathing (under normal/sea level conditions and under the hypobaric, hypoxic conditions present at high altitude) are described in this Chapter. The occurrence of Acute Mountain Sickness (AMS) in subjects who travel form near sea level to altitudes above 3000m is common but its pathophysiology not well understood. The background research into AMS and its treatment and prevention are also covered in Chapter 1. Chapter 2 describes the equipment and methods used in this research, including the polysomnographic equipment used to record sleep and breathing at sea level and the high altitude locations, the portable blood gas analyser used in Nepal and the equipment and methodology used to measure each individual’s ventilatory response to hypoxia and hypercapnia at sea level before ascent to the high altitude locations. Chapter 3 reports the findings on the changes to sleep at high altitude, with particular focus on changes in the amounts of total sleep, the duration of each sleep stage and its percentage of total sleep, and the number and causes of arousals from sleep that occurred during sleep at increasing altitudes. The lightest stage of sleep, Stage 1 non-rapid eye movement (NREM) sleep, was increased, as expected with increases in altitude, while the deeper stages of sleep (Stages 3 and 4 NREM sleep, also called slow wave sleep), were decreased. The increase in Stage 1 NREM in this research is in agreement with all previous findings. However, slow wave sleep, although decreased, was present in most of our subjects at all altitudes in Nepal; this finding is in contrast to most previous work, which has found a very marked reduction, even absence, of slow wave sleep at high altitude. Surprisingly, unlike experimental animal studies of chronic hypoxia, REM sleep was well maintained at all altitudes. Stage 2 NREM and REM sleep, total sleep time, sleep efficiency and spontaneous arousals were maintained at near sea level values. The total arousal index was increased with increasing altitude and this was due to the increasing severity of periodic breathing as altitude increased. An interesting finding of this research was that fewer than half the periodic breathing apneas and hypopneas resulted in arousal from sleep. There was a minor degree of upper airway obstruction in some subjects at sea level but this was almost resolved by 3500m. Chapter 4 reports the findings on the effects on breathing during sleep of the progressive increase of altitude, in particular the occurrence of periodic breathing. This Chapter also reports the results of changes to arterial blood gases as subjects ascended to higher altitudes. As expected, arterial blood gases were markedly altered at even the lowest altitude in Nepal (1400m) and this change became more pronounced at each new, higher altitude. Most subjects developed periodic breathing at high altitude but there was a wide variability between subjects as well as variability in the degree of periodic breathing that individual subjects developed at different altitudes. Some subjects developed periodic breathing at even the lowest altitude and this increased with increasing altitude; other subjects developed periodic breathing at one or two altitudes, while four subjects did not develop periodic breathing at any altitude. Ventilatory responses to hypoxia and hypercapnia, measured at sea level before departure to high altitude, was not significantly related to the development of periodic breathing when the group was analysed as a whole. However, when the subjects were grouped according to the steepness of their ventilatory response slopes, there was a pattern of higher amounts of periodic breathing in subjects with steeper ventilatory responses. Chapter 5 reports the findings of an experimental study carried out in the University of California, San Diego, Barcroft Laboratory on White Mountain in California. Seven subjects drove from sea level to 3800m in one day and stayed at this altitude for two nights. On one of the nights the subjects slept using a non-invasive positive pressure device via a face mask and this was found to significantly improve the sleeping oxyhemoglobin saturation. The use of the device was also found to eliminate the symptoms of Acute Mountain Sickness, as measured by the Lake Louise scoring system. This finding appears to confirm the hypothesis that lower oxygen saturation, particularly during sleep, is strongly correlated to the development of Acute Mountain Sickness and may represent a new treatment and prevention strategy for this very common high altitude disorder.

Doctor of Philosphy (PhD) / This thesis describes the work carried out during four treks, each over 10-11 days, from 1400m to 5000m in the Nepal Himalaya and further work performed during several two-night sojourns at the Barcroft Laboratory at 3800m on White Mountain in California, USA. Nineteen volunteers were studied during the treks in Nepal and seven volunteers were studied at White Mountain. All subjects were normal, healthy individuals who had not travelled to altitudes higher than 1000m in the previous twelve months. The aims of this research were to examine the effects on sleep, and the ventilatory patterns during sleep, of incremental increases in altitude by employing portable polysomnography to measure and record physiological signals. A further aim of this research was to examine the relationship between the ventilatory responses to hypoxia and hypercapnia, measured at sea level, and the development of periodic breathing during sleep at high altitude. In the final part of this thesis the possibility of preventing and treating Acute Mountain Sickness with non-invasive positive pressure ventilation while sleeping at high altitude was tested. Chapter 1 describes the background information on sleep, and breathing during sleep, at high altitudes. Most of these studies were performed in hypobaric chambers to simulate various high altitudes. One study measured sleep at high altitude after trekking, but there are no studies which systematically measure sleep and breathing throughout the whole trek. Breathing during sleep at high altitude and the physiological elements of the control of breathing (under normal/sea level conditions and under the hypobaric, hypoxic conditions present at high altitude) are described in this Chapter. The occurrence of Acute Mountain Sickness (AMS) in subjects who travel form near sea level to altitudes above 3000m is common but its pathophysiology not well understood. The background research into AMS and its treatment and prevention are also covered in Chapter 1. Chapter 2 describes the equipment and methods used in this research, including the polysomnographic equipment used to record sleep and breathing at sea level and the high altitude locations, the portable blood gas analyser used in Nepal and the equipment and methodology used to measure each individual’s ventilatory response to hypoxia and hypercapnia at sea level before ascent to the high altitude locations. Chapter 3 reports the findings on the changes to sleep at high altitude, with particular focus on changes in the amounts of total sleep, the duration of each sleep stage and its percentage of total sleep, and the number and causes of arousals from sleep that occurred during sleep at increasing altitudes. The lightest stage of sleep, Stage 1 non-rapid eye movement (NREM) sleep, was increased, as expected with increases in altitude, while the deeper stages of sleep (Stages 3 and 4 NREM sleep, also called slow wave sleep), were decreased. The increase in Stage 1 NREM in this research is in agreement with all previous findings. However, slow wave sleep, although decreased, was present in most of our subjects at all altitudes in Nepal; this finding is in contrast to most previous work, which has found a very marked reduction, even absence, of slow wave sleep at high altitude. Surprisingly, unlike experimental animal studies of chronic hypoxia, REM sleep was well maintained at all altitudes. Stage 2 NREM and REM sleep, total sleep time, sleep efficiency and spontaneous arousals were maintained at near sea level values. The total arousal index was increased with increasing altitude and this was due to the increasing severity of periodic breathing as altitude increased. An interesting finding of this research was that fewer than half the periodic breathing apneas and hypopneas resulted in arousal from sleep. There was a minor degree of upper airway obstruction in some subjects at sea level but this was almost resolved by 3500m. Chapter 4 reports the findings on the effects on breathing during sleep of the progressive increase of altitude, in particular the occurrence of periodic breathing. This Chapter also reports the results of changes to arterial blood gases as subjects ascended to higher altitudes. As expected, arterial blood gases were markedly altered at even the lowest altitude in Nepal (1400m) and this change became more pronounced at each new, higher altitude. Most subjects developed periodic breathing at high altitude but there was a wide variability between subjects as well as variability in the degree of periodic breathing that individual subjects developed at different altitudes. Some subjects developed periodic breathing at even the lowest altitude and this increased with increasing altitude; other subjects developed periodic breathing at one or two altitudes, while four subjects did not develop periodic breathing at any altitude. Ventilatory responses to hypoxia and hypercapnia, measured at sea level before departure to high altitude, was not significantly related to the development of periodic breathing when the group was analysed as a whole. However, when the subjects were grouped according to the steepness of their ventilatory response slopes, there was a pattern of higher amounts of periodic breathing in subjects with steeper ventilatory responses. Chapter 5 reports the findings of an experimental study carried out in the University of California, San Diego, Barcroft Laboratory on White Mountain in California. Seven subjects drove from sea level to 3800m in one day and stayed at this altitude for two nights. On one of the nights the subjects slept using a non-invasive positive pressure device via a face mask and this was found to significantly improve the sleeping oxyhemoglobin saturation. The use of the device was also found to eliminate the symptoms of Acute Mountain Sickness, as measured by the Lake Louise scoring system. This finding appears to confirm the hypothesis that lower oxygen saturation, particularly during sleep, is strongly correlated to the development of Acute Mountain Sickness and may represent a new treatment and prevention strategy for this very common high altitude disorder.

A l'éveil comme au cours du sommeil, en plaine comme en haute altitude, le maintien d'une oxygénation artérielle stable et élevée est un marqueur essentiel d'une bonne réponse physiologique de l'organisme. L'intolérance à l'altitude regroupe des pathologies graves voire fatales dont le développement est en lien direct avec le taux d'oxygénation artériel des sujets. D'autre part, en plaine, la prévalence élevée du syndrome d'apnées obstructives du sommeil (SAOS) incite les chercheurs au développement de modèles d'études spécifiques, permettant d'investiguer les conséquences du principal stimulus du SAOS : l'hypoxie intermittente. La chémosensibilité pourrait avoir un impact important dans ces deux pathologies, ayant pour rôle le maintien des gaz du sang à des valeurs normales, en adaptant la ventilation aux conditions externes ou internes à l'organisme.Les objectifs de ce travail étaient de comprendre l'impact de la chémosensibilité (avec d'autres mécanismes décrits dans la littérature) sur l'oxygénation et la tolérance à l'altitude, d'étudier les effets de la résistance expiratoire sur l'amélioration de l'oxygénation, ainsi que les conséquences de l'hypoxie intermittente chronique sur la plasticité du chémoréflexe.Il en ressort que la chémosensibilité périphérique à l'hypoxie a un impact majeur sur le développement de l'intolérance à l'altitude. Cela semble en outre être un facteur prédictif de la survenue de ces pathologies. En hypoxie, une amélioration efficace de l'oxygénation a été obtenue par l'utilisation d'une résistance expiratoire calibrée à 10 cm H2O permettant l'amélioration de la diffusion alvéolo-capillaire. L'exposition à l'hypoxie intermittente chronique nocturne a provoqué une fragmentation du sommeil ainsi qu'une intensification de la chémosensibilité à l'hypoxie et à l'hypercapnie.Ainsi, une altération de la réponse des corps carotidiens à l'hypoxémie participerait au développement du mal aigu des montagnes et de ses complications, tout en facilitant sa prédiction avant ascension. L'utilisation d'une résistance expiratoire pourrait permettre de combler la désaturation exagérée retrouvée chez les sujets sensibles à l'altitude lors d'un séjour en haute montagne. Il apparaît également que la chémosensiblité périphérique et centrale (CO2 et O2) fasse preuve d'une plasticité importante en réponse à l'hypoxie intermittente nocturne chez des sujets sains. / At awakening and during sleep, at sea level or in high altitude, maintaining a high level in arterial blood oxygenation is a marker for an adaptated physiological response external and internal factors.High altitude illness encompasses pathologies, that sometimes could be fatal, and which seems to be correlated with the level of arterial oxygenation in hypoxia.Secondly, at sea level and in general population, the high prevalence of obstructive sleep apnea syndrome (OSAS) encourage scientists to develop new models for studying consequences of the main OSAS' stimulus: intermittent hypoxia.Chemosensitivity could play an important role in those two different diseases, with regulation of blood gases and homeostasis by controlling ventilation.Our objectives was to investigate (1) impact of chemosensitivity on blood oxygenation and tolerance to high altitude, comparatively to other physiological factors commonly involved, (2) effects of using positive expiratory pressure in order to improve oxygenation in hypoxia, and (3) consequences of chronic exposure to nocturnal intermittent hypoxia on chemoreflexe plasticity.We found that peripheral chemoresponse to hypoxia play a crucial role in high altitude illness development. Moreover, this variable seems to be a predictive factor for those diseases. In hypoxic conditions, using a positive expiratory pressure (10 cmH2O) lead to a significant improve in arterial oxygenation, by increasing pulmonary diffusion. Finally, nocturnal intermittent hypoxia induced significant sleep disturbances and major changes in chemoresponse to hypoxia and hypercapnia.