Although a broad range of neuropsychological deficits have been reported to occur in patients with Obstructive Sleep Apnea Syndrome (OSAS), few studies have examined the executive functions in this patient group. The executive functions provide conscious control of the more basic cognitive functions and play an important role in daily living. They include capacities such as concept formation, planning, cognitive flexibility and resistance to interference. This study compared the performance of groups of moderate and severe OSAS patients with a group of unaffected individuals (N=24), on five tests of executive functioning. Two indices of sleep disordered breathing, sleep fragmentation and . hypoxemia, obtained from overnight polysomnography, were respectively used to categorise participants. ID patients with severe OSAS, executive function deficits were evident, while in those with moderate OSAS these abilities appeared largely intact. Further analyses revealed that the observed findings could not be attributed to differences in vigilance. These results suggest a discontinuity in the manifestation of executive function deficits between moderate and severe OSAS patients. There may be a threshold of OSAS severity, which if exceeded, impairments tend to occur. The magnitude of the impairment in patients with severe OSAS may be sufficient to interfere with daily cognitive functioning. Further research is needed both to replicate these findings and to establish the underlying pathogenesis of these deficits. / Thesis (M.A.)-University of Natal, Pietermaritzburg, 2001.

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.

Sleep related breathing disorders in childhood are increasingly recognised as contributors to morbidity as well as suboptimal physical, mental and social development. The associated cost in social and economic terms is clearly significant. Detection and diagnosis of such disorders can be costly and technically difficult. Multi-parameter monitoring like polysomnography is expensive and inappropriate for mass screening or investigations remote from tertiary centres. A simple and non-invasive cardiovascular approach termed pulse transit time (PTT) is useful in determining the status of upper airways during sleep. This approach employs the measurement of the time delay in the arterial pulse pressure wave from the aortic valve of the heart to a peripheral site. PTT has shown promise to provide quantify inspiratory effort in adults with sleep disordered breathing (SDB) and can then be an effective monitoring tool in children. Initial investigations explore the parameters that can confound the PTT measurements of a child. This work provides an estimate of the expected PTT ranges from infancy to childhood. Thereafter, overnight PTT recordings were performed in conjunction with PSG studies to corroborate evidence for its capability in paediatric respiratory studies. The results show that PTT has the ability to identify abnormal respiratory events during sleep. Furthermore, the use of PTT can differentiate the nature of respiratory events as obstructive or central. Technological considerations to improve the robustness of PTT measure to be used not only in cardiorespiratory but also cardiovascular studies on children were also illustrated. Preliminary findings obtained here suggest that the properties of PTT show promise as a predictor for obstructive sleep apnoea. There is a need to bridge the gap of providing quality SDB diagnosis and yet accommodating requirements for a robust screening measure. PTT has demonstrated its suitability and utility as a measure to play a role in the investigation and monitoring of treatment in this area.

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.

Content removed due to copyright restrictions: Marshall, N. S., Neill, A. M., Campbell, A. J., & Sheppard, D. S. (2005). Randomised controlled crossover trial of humidified continuous positive airway pressure in mild obstructive sleep apnoea. Thorax, 60(5), 427-432. Marshall, N. S., Gander, P. H., & Neill, A. M. (2003). Obstructive sleep apnoea and risk of motor vehicle accident: A perspective. New Zealand Medical Journal, 116(1176) / The practice of sleep medicine is expanding and evolving rapidly, often ahead of the evidence base to support clinical practice. Obstructive Sleep Disordered Breathing (SDB) is a condition characterised by repetitive airway collapse causing harmful intermittent blood oxygen desaturations and fragmented sleep. When combined with daytime sleepiness it is known as Obstructive Sleep Apnoea Syndrome (OSAS). Continuous Positive Airway Pressure (CPAP) eliminates SDB by pneumatically splinting open the airway with positive air pressure applied through the nose and/or mouth. CPAP effectively reduces daytime sleepiness in patients with severe OSAS. However, doubt remains as to the effectiveness of CPAP in the majority of patients with mild-moderate OSAS. The effects of CPAP were compared to a placebo CPAP during a three week crossover Randomised Controlled Trial (RCT) that included 31 mild-moderate OSAS patients. CPAP effectively eliminated SDB (when worn) and moderately improved subjective sleepiness. But. it did not improve objective wakefulness, mood, psychomotor function, or quality of life. Patients who were extremely sleepy at baseline tended to gain the most placebo adjusted benefit from treatment. A systematic review and meta-analysis aimed to gather and objectively combine all relevant RCT studies to find our whether CPAP reduced sleepiness in patients with mild-moderate OSAS. Seven trials were combined and showed that both subjective sleepiness and objective wakefulness were slightly improved by CPAP therapy. Objective sleepiness was not improved by CPAP. It is not clear from these two studies that treating mild-moderate OSAS with CPAP is an effective use of resources. CPAP effectiveness might be limited by sub-optimal compliance. C-Flex aims to improve compliance by modulating pressure during exhalation. C-Flex was compared to CPAP during a pilot RCT that included 19 patients with severe OSAS. C-Flex was associated with a non-significant increase in compliance of 1.7 hours/night compared to CPAP. However, this increase in compliance was not associated with better daytime patient outcomes. Further experiments are proposed as a result of our pilot RCT. This thesis helps expand evidence-based sleep medicine. Practitioners need to be vigilant, ensuring that treatments are effective in the patients groups in which they are being used (clinical drift), and that new treatments are not adopted without superiority over existing treatments (technological drift).

Content removed due to copyright restrictions: Marshall, N. S., Neill, A. M., Campbell, A. J., & Sheppard, D. S. (2005). Randomised controlled crossover trial of humidified continuous positive airway pressure in mild obstructive sleep apnoea. Thorax, 60(5), 427-432. Marshall, N. S., Gander, P. H., & Neill, A. M. (2003). Obstructive sleep apnoea and risk of motor vehicle accident: A perspective. New Zealand Medical Journal, 116(1176) / The practice of sleep medicine is expanding and evolving rapidly, often ahead of the evidence base to support clinical practice. Obstructive Sleep Disordered Breathing (SDB) is a condition characterised by repetitive airway collapse causing harmful intermittent blood oxygen desaturations and fragmented sleep. When combined with daytime sleepiness it is known as Obstructive Sleep Apnoea Syndrome (OSAS). Continuous Positive Airway Pressure (CPAP) eliminates SDB by pneumatically splinting open the airway with positive air pressure applied through the nose and/or mouth. CPAP effectively reduces daytime sleepiness in patients with severe OSAS. However, doubt remains as to the effectiveness of CPAP in the majority of patients with mild-moderate OSAS. The effects of CPAP were compared to a placebo CPAP during a three week crossover Randomised Controlled Trial (RCT) that included 31 mild-moderate OSAS patients. CPAP effectively eliminated SDB (when worn) and moderately improved subjective sleepiness. But. it did not improve objective wakefulness, mood, psychomotor function, or quality of life. Patients who were extremely sleepy at baseline tended to gain the most placebo adjusted benefit from treatment. A systematic review and meta-analysis aimed to gather and objectively combine all relevant RCT studies to find our whether CPAP reduced sleepiness in patients with mild-moderate OSAS. Seven trials were combined and showed that both subjective sleepiness and objective wakefulness were slightly improved by CPAP therapy. Objective sleepiness was not improved by CPAP. It is not clear from these two studies that treating mild-moderate OSAS with CPAP is an effective use of resources. CPAP effectiveness might be limited by sub-optimal compliance. C-Flex aims to improve compliance by modulating pressure during exhalation. C-Flex was compared to CPAP during a pilot RCT that included 19 patients with severe OSAS. C-Flex was associated with a non-significant increase in compliance of 1.7 hours/night compared to CPAP. However, this increase in compliance was not associated with better daytime patient outcomes. Further experiments are proposed as a result of our pilot RCT. This thesis helps expand evidence-based sleep medicine. Practitioners need to be vigilant, ensuring that treatments are effective in the patients groups in which they are being used (clinical drift), and that new treatments are not adopted without superiority over existing treatments (technological drift).

Methadone is a long acting mu-opioid and is the most effective treatment for heroin addiction. However, opioids depress respiration and methadone maintenance treatment (MMT) patients have a higher mortality rate than the general population. Teichtahl et al conducted a pilot study and found 6 out of 10 MMT patients had central sleep apnea (CSA). But no definite conclusions were made regarding the prevalence and possible pathogenesis of CSA in the patients due to the small sample size and lack of blood toxicology data. The present project aims to confirm the preliminary results and further quantify the sleep disordered breathing (SDB) in stable MMT patients and to delineate the pathogenesis involved. (For complete abstract open document)