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Obstructive sleep apnoea (OSA) is a common respiratory disorder characterised by repetitive periods of upper airway (UA) collapse during sleep. OSA is more common in males and the obese but the reasons why remain poorly understood. Abdominal obesity, particularly common in males, is likely to indirectly modulate the amount of tension (tracheal traction) exerted on the UA by the trachea and other intrathoracic structures, potentially leading to increased UA collapsibility. Other factors such as lung volume changes with obesity, altered drive to UA muscles and exaggerated arousal responses are also likely to contribute to UA instability. An investigation of these potential contributing factors forms the basis of this thesis. In the first study, the effect of external abdominal compression on UA collapsibility during sleep was investigated in a group of obese male OSA patients. A large pneumatic cuff wrapped around the abdomen was inflated to increase intra-abdominal pressure, aiming to produce an upward force on the diaphragm, designed to reduce axial tension on the UA. Abdominal compression increased end-expiratory gastric (PGA) and end-expiratory transdiaphragmatic (PDI) pressure by ~50% and produced a significant rise in UA collapsibility compared to the cuff deflated condition. These data support that increased intra-abdominal pressure has a negative effect on UA function during sleep. This effect may help explain why obesity is the leading risk factor for OSA and why OSA affects men more than women, given that abdominal obesity is particularly common in obese males. In the second study, differences in minimum expiratory (tonic) diaphragm activity during wakefulness were compared between 8 obese OSA patients and 8 healthyweight controls. Changes in tonic diaphragm activity and lung volume following sleep onset were also compared between the two groups. There was no evidence of increased tonic diaphragmatic activity during wakefulness in obese OSA patients to support significant diaphragmatic compensation for abdominal compressive effects of obesity. There were small decrements in lung volume following sleep onset in both groups (<70 ml), with significantly greater lung volume and diaphragmatic EMG decrements when sleep onsets were immediately followed by respiratory events. While lung volume decrements at sleep onset were relatively small, this does not discount that UA function is not more sensitive to effects of reduced lung volume in obese OSA patients. To more closely investigate the potential interactive effects of obesity on physiological variables likely influencing UA function, the third study investigated the temporal relationships between a comprehensive range of relevant physiological variables leading into and following the termination of obstructive apnoeas during sleep in 6 obese OSA patients. Prior to UA obstruction, diaphragm and genioglossus muscle activity decreased, while UA resistance increased. Lung volume and end-expiratory PGA and end-expiratory PDI also fell during this period, consistent with diaphragm ascent. There was a substantial increase in ventilation, muscle activity and lung volume immediately following the termination of obstructive events. Respiratory events and arousals occurred in close temporal proximity prior to and following obstructive apnoeas, supporting that cyclical respiratory events and arousals may both help to perpetuate further events. The results from this study support that there is a ‘global’ loss in respiratory drive to UA dilator and pump muscles precipitating obstructive respiratory events. The associated decreases in UA dilator muscle activity and lung volume may therefore both contribute to the propensity for the UA to obstruct. In summary, increased intra-abdominal pressure was shown to negatively impact UA airway collapsibility during sleep. A decrease in lung volume at sleep onset and prior to UA obstruction further support that lung volume decrement, coincident with a decline in overall respiratory drive, potentially contributes to the propensity for airway obstruction. Further studies are needed to elucidate the relative contribution of relatively small changes in lung volume versus changes in respiratory and UA muscle activity per se on UA patency in OSA patients. / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2010

Obstructive sleep apnoea (OSA) is characterised by repetitive reductions or pauses in breathing during sleep due to upper airway narrowing or closure. Due to disruption to normal sleep patterns, many patients with OSA suffer from increased daytime sleepiness. Epidemiological studies have established a link between OSA and driver fatigue and accidents, generally showing a two to seven times increased risk of road traffic accidents in non-commercial drivers with OSA. There is emerging evidence that commercial drivers have a higher prevalence of OSA than the general population, being predominately male, middle-aged and overweight, three important risk factors for OSA. However, little is known about the relationship between OSA and driver sleepiness in commercial drivers, whether road accidents are increased in commercial drivers with OSA, and whether OSA interacts with other fatigue promoting factors, such as sleep deprivation, to further escalate road accident risk. One thousand randomly selected commercial drivers were surveyed in the field. In addition, 61 randomly selected NSW commercial drivers had in hospital sleep studies and daytime performance testing, including a PC based driving simulator task. The prevalence of OSA, defined as Respiratory Disturbance Index (RDI) < 10, was approximately 50% in NSW commercial drivers. Approximately one quarter of the drivers reported pathological daytime sleepiness, and 12-14% had both OSA and pathological daytime sleepiness. A diagnosis of OSA was the most important factor predicting excessive daytime sleepiness in these drivers: OSA was more important than 15 other work-related, lifestyle and medical factors that could be expected to promote, or be associated with, daytime sleepiness. Drivers with sleep apnoea syndrome (both OSA and pathological daytime sleepiness) had an increased driving accident risk, using driving simulator and daytime performance testing as proxy measures for accident risk. These results demonstrate the importance of OSA as a cause of driver fatigue in commercial drivers and suggest that all commercial drivers should be screened for the presence of sleep apnoea syndrome in order to potentially reduce road accident risk through treatment. A separate, but related body of work examined the combined effects of mild OSA and other fatigue promoting factors (sleep deprivation and circadian influences) on driving performance. Twenty nine subjects, consisting of a group with mild OSA and a group of non-OSA controls, were tested on several occasions throughout the night and day using an intensive performance battery, under both baseline conditions and after a period of 36 hours of total sleep deprivation. The results suggest that drivers with mild OSA are not different to the control group in their response to sleep deprivation or time of day influences. However, the subjects with mild OSA were less aware of their impairment due to sleep deprivation, which is of concern if drivers with OSA are relying on their subjective awareness of fatigue to make decisions about when to stop driving. A final perspective on OSA and driver fatigue is provided through a clinical case series of seven fall-asleep fatality associated MVA�s associated with unrecognised or under-treated sleep disorders. As well as demonstrating the day to day potential for devastating road accidents due, at least in part, to un-recognised or untreated sleep disorders, these cases also serve to highlight some of the current medico-legal controversies and difficulties in this area of driver fatigue. In conclusion, this body of work has provided novel information about the epidemiology and implications of OSA in commercial drivers, and about how OSA interacts with other fatigue promoting factors. Finally, it has explored some of the medico-legal issues that relate to sleep disorders and driver fatigue. As well as providing much needed information in the area of driver fatigue, at the same time this work raises many more questions and suggests areas of future research. For instance, such research should examine the relationship between objective accident rates and OSA/sleep apnoea syndrome in commercial drivers, the interaction between mild sleep apnoea syndrome and other fatigue risk factors, and driver perception of sleepiness prior to sleep onset in drivers with sleep disorders.

Obstructive sleep apnoea (OSA) is a common condition characterized by recurrent complete and partial upper airway obstruction. OSA sufferers have been shown to have a significantly smaller upper airway lumen compared to non-OSA sufferers. However, non-anatomical factors of sleep stage, arousability and neuromechanical responses to airway occlusion and chemosensitivity are likely to play a significant part in influencing OSA severity across the night. An exploration of these non-anatomical factors forms the basis for the experiments in this thesis. In the first experimental chapter presented in this thesis, a detailed retrospective epoch by epoch analysis of nocturnal polysomnography in 253 patients referred to a clinical sleep service was performed to examine differences in sleep apnoea severity and arousal indices across the different stages of sleep, while controlling for posture. Both patients with and without OSA demonstrated significant reductions in respiratory and arousal event frequencies from stage 1 to 4 with intermediate frequencies in REM sleep. Lateral posture was also associated with significant improvements in OSA and arousal frequencies, with an effect size comparable to that of sleep stage. The majority of patients showed significant reductions in OSA severity during slow wave sleep. In non-REM sleep, there was a strong correlation between OSA severity and arousal frequency. These results confirm in a large group of patients, a strong sleep stage dependence of both OSA and arousal frequencies. The second study in this thesis explores the development of a CO2 stabilising or ‘clamp’ device to enable the provision of positive airway pressure, and by proportional rebreathing, the maintenance of relatively constant end-tidal CO2 despite significant hyperventilation. Healthy volunteers performed brief periods of significant voluntary hyperventilation at 2 levels of CPAP with the rebreathing function off and with active CO2 clamping in randomized order. Compared to CPAP alone, the device substantially attenuated hypocapnia associated with hyperventilation. The third study of the thesis was designed to investigate if increasing and stabilizing end-tidal CO2 could improve obstructive breathing patterns during sleep. 10 patients with severe OSA underwent rapid CPAP dialdown from therapeutic to a sub-therapeutic level to experimentally induce acute, partial upper airway obstruction over 2 minute periods repeated throughout the night. The CO2 clamp device developed and validated in Study 2 was used to determine whether during periods of partial upper airway obstruction with severe flow limitation, (1) increased end-tidal CO2 resulted in improved airflow and ventilation and (2) clamping end-tidal CO2 lessened post-arousal ventilatory undershoot. Three conditions were studied in random order: no clamping of CO2, clamping of end-tidal CO2 3-4 mmHg above eucapnic levels during the pre-dialdown baseline period only, and clamping of CO2 above eucapnia during both baseline and dialdown periods. Elevated CO2 in the baseline period alone or in the baseline and dialdown periods together resulted in significantly higher peak inspiratory flows and ventilation compared to the no clamp condition. Breath-by-breath analysis immediately pre- and post-arousal showed higher end-tidal CO2 despite hyperventilation immediately post-arousal and attenuation of ventilatory undershoot in CO2 versus non-CO2 clamped conditions. These results support that modulation of ventilatory drive by changes in pre- and post-arousal CO2 are likely to importantly influence upper airway and ventilatory stability in OSA. The fourth study was designed to explore several possible pathophysiological mechanisms whereby obstructive sleep apnoea is improved in stages 3 & 4 (slow wave) versus stage 2 sleep. 10 patients with severe OSA who demonstrated significant reductions in OSA frequency during slow wave sleep on diagnostic investigation were studied. Patients underwent rapid dialdowns from therapeutic CPAP to 3 different pre-determined sub-therapeutic pressures to induce partial airway obstruction and complete airway occlusions in a randomised sequence during the night in both stage 2 and slow wave sleep. Partial airway obstructions and complete occlusions were maintained until arousal occurred or until 2 minutes had elapsed, whichever came first. After airway occlusions, time to arousal, peak pre-arousal negative epiglottic pressure and the rate of ventilatory drive augmentation were significantly greater, suggesting a higher arousal threshold and ventilatory responsiveness to respiratory stimuli during slow wave compared to stage 2 sleep. Post dialdowns, the likelihood of arousal was lower with less severe dialdowns and in slow wave compared to stage 2 sleep. Respiratory drive measured by epiglottic pressure progressively increased post-dialdown, but did not translate into increases in peak flow or ventilation pre-arousal and was not different between sleep stages. These data suggest that while arousal time and propensity following respiratory challenge are altered by sleep depth, there is little evidence to support that upper airway and ventilatory compensation responses to respiratory load are fundamentally improved in slow wave compared to stage 2 sleep. In summary, sleep stage, arousal threshold and chemical drive appear to strongly influence upper airway and ventilatory stability in OSA and are suggestive of important non-anatomical pathogenic mechanisms in OSA.

Obstructive sleep apnoea (OSA) is a common disorder characterized by repetitive closure of the upper airway during sleep and associated with significant adverse health effects including hypertension, heart disease and stroke. Current treatment with continuous positive airway pressure (CPAP) is highly effective but reduced compliance levels have resulted in suboptimal outcomes. Oral appliances such as mandibular advancement splints (MAS) are an alternative treatment and have potential advantages including greater patient compliance, comfort and portability. Although they have been shown to be successful across all categories of OSA severity, overall they are less effective than CPAP. A key limitation to its more widespread use has been the inability to predict which patients will be a treatment success. Prediction of treatment outcome would greatly enhance both MAS utilization and overall OSA management. However, little is known about the mechanisms of action of MAS therapy and a more detailed understanding is likely to improve patient selection and outcome. The aim of this thesis is to improve the prediction of treatment outcome through improved understanding of the mechanisms and site(s) of action of MAS therapy during sleep, through extrapolating this knowledge into daytime prediction tests and by developing prediction equations which can be tested prospectively. The work in this thesis presents novel ideas and findings. It is the first to examine and find that MAS therapy improves upper airway collapsibility during sleep. The site(s) of upper airway collapse was also examined and found to predict treatment outcome. Primary oropharyngeal collapse during sleep predicted treatment success and this was extrapolated into a simple daytime test hypothesized to reflect oropharyngeal function. These primary oropharyngeal collapsers were found to have characteristic awake flow-volume curves and this was then studied prospectively. Cephalometric X-rays and anthropomorphic measurements were also evaluated to formulate prediction equations for treatment outcome with MAS. These new findings together with their implications for clinical practice and future research are then summarized. It is concluded, however, that although many advancements have been made, the mechanisms of MAS action and prediction of treatment outcome remain incompletely understood reflecting the complex pathophysiology of the upper airway.

Obstructive sleep apnoea (OSA) is characterised by repetitive reductions or pauses in breathing during sleep due to upper airway narrowing or closure. Due to disruption to normal sleep patterns, many patients with OSA suffer from increased daytime sleepiness. Epidemiological studies have established a link between OSA and driver fatigue and accidents, generally showing a two to seven times increased risk of road traffic accidents in non-commercial drivers with OSA. There is emerging evidence that commercial drivers have a higher prevalence of OSA than the general population, being predominately male, middle-aged and overweight, three important risk factors for OSA. However, little is known about the relationship between OSA and driver sleepiness in commercial drivers, whether road accidents are increased in commercial drivers with OSA, and whether OSA interacts with other fatigue promoting factors, such as sleep deprivation, to further escalate road accident risk. One thousand randomly selected commercial drivers were surveyed in the field. In addition, 61 randomly selected NSW commercial drivers had in hospital sleep studies and daytime performance testing, including a PC based driving simulator task. The prevalence of OSA, defined as Respiratory Disturbance Index (RDI) < 10, was approximately 50% in NSW commercial drivers. Approximately one quarter of the drivers reported pathological daytime sleepiness, and 12-14% had both OSA and pathological daytime sleepiness. A diagnosis of OSA was the most important factor predicting excessive daytime sleepiness in these drivers: OSA was more important than 15 other work-related, lifestyle and medical factors that could be expected to promote, or be associated with, daytime sleepiness. Drivers with sleep apnoea syndrome (both OSA and pathological daytime sleepiness) had an increased driving accident risk, using driving simulator and daytime performance testing as proxy measures for accident risk. These results demonstrate the importance of OSA as a cause of driver fatigue in commercial drivers and suggest that all commercial drivers should be screened for the presence of sleep apnoea syndrome in order to potentially reduce road accident risk through treatment. A separate, but related body of work examined the combined effects of mild OSA and other fatigue promoting factors (sleep deprivation and circadian influences) on driving performance. Twenty nine subjects, consisting of a group with mild OSA and a group of non-OSA controls, were tested on several occasions throughout the night and day using an intensive performance battery, under both baseline conditions and after a period of 36 hours of total sleep deprivation. The results suggest that drivers with mild OSA are not different to the control group in their response to sleep deprivation or time of day influences. However, the subjects with mild OSA were less aware of their impairment due to sleep deprivation, which is of concern if drivers with OSA are relying on their subjective awareness of fatigue to make decisions about when to stop driving. A final perspective on OSA and driver fatigue is provided through a clinical case series of seven fall-asleep fatality associated MVA�s associated with unrecognised or under-treated sleep disorders. As well as demonstrating the day to day potential for devastating road accidents due, at least in part, to un-recognised or untreated sleep disorders, these cases also serve to highlight some of the current medico-legal controversies and difficulties in this area of driver fatigue. In conclusion, this body of work has provided novel information about the epidemiology and implications of OSA in commercial drivers, and about how OSA interacts with other fatigue promoting factors. Finally, it has explored some of the medico-legal issues that relate to sleep disorders and driver fatigue. As well as providing much needed information in the area of driver fatigue, at the same time this work raises many more questions and suggests areas of future research. For instance, such research should examine the relationship between objective accident rates and OSA/sleep apnoea syndrome in commercial drivers, the interaction between mild sleep apnoea syndrome and other fatigue risk factors, and driver perception of sleepiness prior to sleep onset in drivers with sleep disorders.

Aims: LDL oxidation plays an important role in the initiation and progression of atherosclerosis. HDL impedes oxidation, glycation and glycoxidation in vitro and there is evidence to suggest paraoxonase-1 (PON1) plays an important role in this. 1. In patients with dyslipidaemia treated with statins, I assessed the relationship of serum PON1 activity with in vitro HDL antioxidant capacity, susceptibility of LDL to oxidation and the protection offered by HDL. 2. I studied the effect of the presence and severity of obstructive sleep apnoea (OSA) in morbidly obese patients on HDL anti-oxidant and anti-inflammatory functions. 3. I investigated the influence of extended release niacin/ laropiprant (ERN/LRP) versus placebo in patients who had persistent dyslipidaemia despite receiving high doses of potent statins. I assessed the effect of ERN/LRP on mediators of vascular inflammation and HDL's in vitro anti-oxidant function. Methods: 1. LDL isolated from dyslipidemic patients was incubated with and without HDL, in the presence of Cu2+. Similarly isolated HDL was incubated alone. Lipid peroxides (LPO) generated over 3 hours were measured. Patients were divided into 2 groups based on median serum PON1 activity. 2. 41 morbidly obese patients were divided into two groups based on the presence or absence of OSA ("OSA" and "no OSA" group) or on severity of OSA (high or low apnoea-hypoapnoea index (AHI) groups). I studied HDL's ability to protect itself from in vitro oxidation and measured serum PON1 activity, tumor necrosis factor alpha (TNFalpha) and intercellular adhesion molecule 1 (ICAM1). 3. This was a randomised double blind cross over trial, where I studied the effect of ERN/LRP compared to placebo in 27 patients who had high LDL-C inspite of maximum tolerated doses of statins. I measured lipid profile, apolipoproteins, cholesteryl ester transport protein (CETP) activity, paraoxonase 1 activity (PON1), oxidised LDL (oxLDL) and related mediators of vascular inflammation. I also examined the capacity of HDL to protect LDL from in vitro oxidation. Results and conclusion: 1. In statin treated dyslipidemic patients the capacity of HDL to protect itself and LDL from oxidation in vitro is significantly better in individuals with higher serum PON1 activity. 2. The capacity of HDL to protect itself from in vitro oxidation in morbidly obese patients is reduced with onset and severity of OSA. The differences in TNFalpha and ICAM1 levels may suggest endothelial dysfunction due to OSA. Oxidative damage of PON1 attributable to OSA could be a mechanism for HDL and endothelial dysfunction. 3. Treatment with ERN/LRP resulted in a significant improvement in HDL-C but did not affect HDL's in vitro anti-oxidant function in patients who had persistent dyslipidaemia despite high doses of potent statins. For the first time I have shown that ERN/LRP reduces mediators of vascular inflammation.

Background. Obstructive Sleep Apnoea (OSA) is associated with an increase in nocturnal gastro-oesophageal reflux (nocturnalGOR) events and symptoms, however the mechanism for this remains undefined. Treatment of OSA with continuous positive airway pressure (CPAP) has been shown to reduce nocturnalGOR in individuals with OSA however the reasons for this reduction are not clear. The combination of OSA and nocturnalGOR could be particularly problematic for individuals who have had a lung transplant in whom Bronchiolitis Obliterans Syndrome (BOS) limits survival. It is thought that GOR plays a role in the development of BOS in these individuals. Methods and Results. Five interrelated studies were undertaken. The first two studies sought to determine and compare the prevalence and risk factors of nocturnalGOR in OSA patients with the general population. To do this, a GOR questionnaire was completed by 2,042 members of the general community as part of the Busselton Health Survey and by 1,116 patients with polysomnography-diagnosed OSA. Risk of OSA in the general population was determined using a standardised sleep questionnaire. 137 of the OSA patients completed the questionnaire before and after treatment with CPAP. The prevalence of nocturnalGOR symptoms reported more than once a week (frequent symptoms) was greater in OSA patients (10.1%) than the general population (5.8%) (p<0.001), in individuals from the general population at high (11.2%) than low risk of OSA (4.5%) (p<0.001) and in patients with severe (14.7%) than mild OSA (5.2%) (p<0.001). Treatment of OSA with CPAP decreased the prevalence of frequent nocturnalGOR from 9.0% to 3.8% (p=0.04). In the general population, high risk of OSA was independently associated with a 2.4-fold increased risk of frequent ABSTRACT vi nocturnalGOR symptoms than low risk. In the OSA group, disease severity was independently associated with nocturnalGOR symptoms, with an adjusted odds ratio of 1.7 for frequent nocturnalGOR symptoms.

Obstructive Sleep Apnoea (OSA) is a disease characterised by repetitive upper airway obstructions which are manifest by desaturation and arousal from sleep. It has been known for many years that this interruption to the normal architecture of sleep may present to the clinician as excessive daytime somnolence often with a complaint of difficulties with concentration and short term memory. Previous work had demonstrated a relationship between variables of cognitive dysfunction in patients with obstructive sleep apnoea, however, little was known about which components of the syndrome contributed to this outcome and whether specific clinical thresholds of sleep disordered breathing could be defined for the development of cognitive dysfunction. In the context of this body of work cognitive dysfunction is defined as: a level of cognitive performance below normal derived values for a given cognitive test, when the subjects performance is controlled for age, sex and level of education.