Abstract not available

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.

Sleep disruption has been implicated in morbidity after major surgery since 1974. Sleep-related upper airway obstruction has been associated with death after upper airway surgery and profound episodic hypoxaemia in the early postoperative period. There is also evidence for a rebound in rapid eye movement (REM) sleep that might be contributing to an increase in episodic sleep-related hypoxaemic events later in the first postoperative week. Speculation regarding the role of REM sleep rebound in the generation of late postoperative morbidity and mortality has evolved into dogma without any direct evidence to support it. The research presented in this thesis involved two main areas: a search for evidence of a clinically important contribution of REM sleep rebound to postoperative morbidity, and a re-examination of the role of sleep in the causation of postoperative episodic hypoxaemic events. To assess the latter, a relationship between airway obstruction under anaesthesia and the severity of sleep-disordered breathing was sought. In 148 consecutive sleep clinic patients, 49% of those with sleep-disordered breathing (SDB) had a number of events in non-rapid eye movement sleep (NREM) that was greater than or equal to that in REM and 51% had saturation nadirs in NREM that were equal to or worse than their nadirs in REM. This suggests SDB is not a REM-predominant phenomenon for most patients. Of 1338 postoperative deaths occurring over 6.5 years in one hospital only 37 were unexpected, most of which were one or two days after surgery with no circadian variation in the time of death, casting further doubt on the potential role of REM rebound. Five of nine subjects studied preoperatively had moderately severe SDB. Unrecognised and significant SDB is common in middle-aged and elderly patients presenting for surgery suggesting overall perioperative risk of important adverse events from SDB is probably small. In 17 postoperative patients, sleep macro-architecture was variably altered with decreases in REM and slow wave sleep while stage 1 sleep and a state of pre-sleep onset drowsiness, both associated with marked ventilatory instability, were increased. Sleep micro-architecture was also changed with an increase in power in the alpha-beta electroencephalogram range. These micro-architectural changes result in ambiguity in the staging of postoperative sleep that may have affected the findings of this and other studies. Twenty-four subjects with airway management difficulty under anaesthesia were all found to have some degree of SDB. Those with the most obstruction-prone airways while anaesthetised had a very high incidence of severe SDB. Such patients warrant referral to a sleep clinic.

Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a serious sleep disordered affecting up to 24% of men and 9% of woman in the middle aged population. The current standard for the OSAHS diagnosis is Polysomnography (PSG), which refers to the continuous monitoring of multiple physiological variables over the course of a night. The main outcomes of the PSG test are the OSAHS severity measures, such as the Respiratory Disturbance Index (RDI), Arousal Index, Latencies and other information to determine the macro sleep architecture (MSA), which is defined by Wake, Rapid-eye-movement (REM) and non-REM states of sleep. The MSA results are essential for computing the diagnostic measures reported in a PSG. The existing methods of the MSA analysis require the recording of 5-7 electrophysiological signals, including the Electroencephalogram (EEG), Electroculogram (EOG), and the Electromyogram (EMG). Sleep clinicians have to depend on the manual scoring of the overnight data records using the criteria given by Rechtschaffen and Kales (R&K, 1968). The manual analysis of MSA is tedious, subjective and suffers from inter- and intra-scorer variability. Additionally, the RDI and the Apnea-Hypopnea Index (AHI) parameters although used as the primary measures of the OSAHS severity, suffers from subjectivity, low reproducibility and a poor correlation with the symptoms of OSAHS. Sleep is essentially a neuropsychological phenomenon, and the EEG remains the best technique for the functional imaging of the brain during sleep. The EEG is the direct result of the neuronal activity of the brain. However, despite the potential, the wealth of information available in the EEG signal remains virtually untapped in current OSAHS diagnosis. Although the EEG is extensively used in traditional sleep analysis, its usage is mainly limited to staging sleep, based on the four-decade old R&K criteria. This thesis addresses these issues plaguing the PSG. We develop a novel, fully-automated algorithm (Higher-order Estimated Sleep States, HESS-algorithm) for the MSA analysis, which requires only one channel of the EEG data. We also develop an objective MSA analysis technique that uses a single, one-dimensional slice of the Bispectrum of the EEG, representing a nonlinear transformation of a system function that can be considered as the EEG generator. The agreement between the human and the proposed technology was found to be in the range of 70%-87%, which are similar to those, possible between expert human scorers. The ability of the HESS algorithm to compute the MSA parameters reliably and objectively will make a dramatic impact on the diagnosis and treatment of OSAHS and other sleep diseases, such as insomnia. The proposed technology uses low-computation-load Bispectrum techniques independent of R&K Criteria (1968) making real-time automated analysis a reality. In the thesis we also propose a new index (the IHSI) to characterise the severity of sleep apnea. The new index is based on the hemispherical asymmetry of the brain and is computed from the EEG coherence analysis. We achieved a significant (p=0.0001) accuracy of up to 91% in classifying patients into apneic and non-apneic group. Our statistical analysis results show that the IHSI carries potential for providing us with a reproducible measure to assist in diagnosing of OSAHS. With the proposed methods in this thesis it may be possible to develop the technology that will not only attempt to screen the OSAHS patients but will be able to provide OSAHS diagnosis with detailed sleep architecture via home based test. These technologies will simplify the instrumentation dramatically and will make possible to extend EEG/MSA analysis to portable systems as well.

Sleep represents a third of our life, from birth to death. Sleep allows our body and mind to rest, and breaking its structure may lead to severe physical and nervous damage. Breathing disorders, like apneas, hypopneas or RERA events, alter the recovering feature of sleep by fragmenting its structure. They usually lead to daytime sleepiness, depression, hypertension, cardiovascular disease,... In order to give the most suitable treatment to a patient, the gold standard polysomnography (PSG) is recorded in a hospital setting and the huge amount of data is visually analyzed the day after. The PSG is expensive, time-consuming for the clinicians and unpleasant for the patient. Thus, portable monitoring devices and automatic analysis methods are welcome. Four physiological parameters are required to score the three breathing disorders mentioned above: nasal airflow, oximetry, arousals and respiratory effort markers. While arousals are defined in the EEG traces, the esophageal pressure is the gold standard but invasive measure of effort. Surrogates (signals) exist for both arousal, like PAT, PTT or ECG, and effort markers, like TAM, PTT or FOT. This thesis was dedicated to a novel one, the maxillo-mandibular movements. This signal is not only able to point arousals and effort, but it has also the capability to distinguish sleep from wake as a mandibular actimeter, like the wrist actigraphy. These three features make it worth of interest. At first, the jaw movements signal essence was extracted, automatic methods 1) to point arousals, 2) to indicate periodic patterns like respiratory effort or salvo of sleep events, 3) to detect and classify apneas, hypopneas and RERA and 4) to separate sleep from wake were developed and evaluated. Then, the sleep apneas/hypopneas and the sleep/wake detectors were then improved by adding the oximetry in a first step. Finally, the nasal airflow brought its potential in both detection and classification of breathing disorders, especially to overcome the inherent classification problem between apneas and hypopneas since the jaw movements sensor is an effort sensor. All the methods developed in this thesis were applied to a huge database of 150 consecutive recordings at the Sleep Laboratory of the University of Liege for sleep apneas and hypopneas detection assessment. Moreover, an APAP device, that applies a regulated pressure throughout a nasal mask to prevent from upper airways collapse, was designed using only features computed from jaw movements in real-time, and showed similar results to the widely tested iS20i from BREAS. In conclusion, the maxillo-mandibular movements signal does bring usefull information about respiratory effort and arousals, and coupled with the nasal flow and oximetry signal provides an accurate detection and classification of sleep apneas, hypopneas and RERA. Besides, this jaw actimeter and its ad-hoc algorithm allows to distinguish sleep from wake. All in all, the jaw movements signal is a very valuable and a unique physiological signal for home sleep studies.

Obstructive sleep apnea syndrome (OSAS) is characterized by snoring, apneas and excessive daytime sleepiness (EDS). Obesity is a risk factor for snoring and sleep apnea, but data on other factors in relation to obesity are ambiguous. Symptoms of sleep apnea in women have not been fully elucidated. OSAS is an important risk factor for cardiovascular disease (CVD). A common feature in patients with CVD and sleep apnea is an increase in systemic inflammation. From the general population 7,051 women ≥ 20 years answered a questionnaire on snoring and sleep disturbances. Habitual snoring was found in 8% of the total population, and influenced by age, obesity and smoking. The highest prevalence (14%) was found in women 50-59 years. In lean women, alcohol dependence was associated with snoring, while physical inactivity was a risk factor for snoring in obese women. Further, 230 snoring women and 170 women regardless of snoring status were investigated with polysomnography, blood sampling and anthropometric measurements. Of these, 132 participants underwent an ocular and endoscopic examination of their upper airways. Several findings in the upper airways characterised normal-weight women with an apnea-hypopnea index (AHI) ≥ 10. In women with BMI of &gt; 25, no pharyngeal characteristics predicted sleep apnea. When adjusting for age, obesity, smoking, AHI and sleep parameters, several aspects of daytime sleepiness correlated to snoring independently of AHI (EDS, falling asleep involuntarily during day, waking up unrefreshed and fatigue). No symptoms correlated to AHI independently of snoring. Blood samples were analysed for systemic inflammation (CRP, TNFα, IL-6, myeloperoxidase (MPO) and lysozyme). Strong correlations were found between obesity and inflammatory markers. AHI and nocturnal hypoxia correlated to all markers except MPO. When adjusting for age, obesity and smoking, only IL-6 and TNFα were independently associated with nocturnal hypoxia. In conclusion, age and obesity influence the prevalence of snoring and sleep apnea in women from the general population. Other risk factors differ according to BMI. Daytime symptoms are independently related to snoring per se. Despite a strong correlation between obesity and inflammation, an independent relationship between sleep apnea and inflammatory markers was found.

Obstructive sleep apnea (OSA) severity is strongly associated with the degree of overnight peripharyngeal fluid accumulation. We hypothesized that intravenous fluid loading would cause upper airway (UA) narrowing or increase the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index; AHI). We employed a controlled, randomized double-crossover experiment in 9 healthy men aged 23-46 years. In the control, subjects were administered approximately 80 ml of normal saline intravenously during sleep. In the intervention, subjects were administered approximately 1850 ml of saline during sleep while wearing compression stockings to localize fluid rostrally. The intervention induced nuchal fluid accumulation, resulting in an increase in neck circumference (+0.1 cm during control, +0.6 cm during intervention, P< 0.01 ) and a decrease in UA cross-sectional area (-0.08 cm2 during control, -0.43 cm2 during intervention, P = 0.023). Although the intervention did not increase the AHI (control AHI = 19.5, intervention AHI = 30.3, P = 0.249), the AHI during the intervention correlated with age (r = 0.8, P < 0.01). Thus, intravenous saline loading during sleep can narrow the UA, which in older men may induce or worsen OSA. Further studies are needed to test this hypothesis.

Obstructive sleep apnea (OSA) severity is strongly associated with the degree of overnight peripharyngeal fluid accumulation. We hypothesized that intravenous fluid loading would cause upper airway (UA) narrowing or increase the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index; AHI). We employed a controlled, randomized double-crossover experiment in 9 healthy men aged 23-46 years. In the control, subjects were administered approximately 80 ml of normal saline intravenously during sleep. In the intervention, subjects were administered approximately 1850 ml of saline during sleep while wearing compression stockings to localize fluid rostrally. The intervention induced nuchal fluid accumulation, resulting in an increase in neck circumference (+0.1 cm during control, +0.6 cm during intervention, P< 0.01 ) and a decrease in UA cross-sectional area (-0.08 cm2 during control, -0.43 cm2 during intervention, P = 0.023). Although the intervention did not increase the AHI (control AHI = 19.5, intervention AHI = 30.3, P = 0.249), the AHI during the intervention correlated with age (r = 0.8, P < 0.01). Thus, intravenous saline loading during sleep can narrow the UA, which in older men may induce or worsen OSA. Further studies are needed to test this hypothesis.

This thesis aimed at developing and evaluating a tailored behavioural sleep medicine intervention for enhanced physical activity and healthy eating in patients with obstructive sleep apnea syndrome (OSAS) and overweight. Participants with moderate or severe OSAS (apnea-hypopnea index ≥15) and obesity (Studies I-II) or overweight (Studies III-IV), treated with continuous positive airway pressure (CPAP) (Studies I-II) or admitted to CPAP treatment (Studies III-IV), were recruited from the sleep clinic at Uppsala University Hospital, Sweden. Semi-structured individual interviews were analysed using qualitative content analysis (Study I). Data on moderate-to-vigorous physical activity (MVPA) and sedentary time were collected with three measurement methods and analysed regarding the level of measurement agreement (Study II). Potential disease-related and psychological correlates for the amount of MVPA, daily steps and sedentary time were explored using multiple linear regression (Study III). Physical activity and eating behaviour changes were examined after a six month behaviour change trial (Study IV). A tailored behavioural sleep medicine intervention targeting physical activity and healthy eating in combination with first- time CPAP treatment was compared with CPAP treatment and advice on the association between weight and OSAS. According to participants’ conceptions, a strong incentive is needed for a change in physical activity and bodily symptoms, external circumstances and thoughts and feelings influence physical activity engagement (Study I). Compared with accelerometry, the participants overestimated the level of MVPA and underestimated sedentary time when using self-reports (Study II). The participants spent 11 hours 45 minutes (71.6% of waking hours) while sedentary. Fear of movement contributed to the variation in steps and sedentary time. Body mass index was positively correlated to MVPA (Study III). The experimental group increased intake of fruit and fish and reduced more weight and waist circumference compared with controls. There were no changes in physical activity (Study IV). The novel tailored behavioural sleep medicine intervention combined with first-time CPAP facilitated eating behaviour change, with subsequent effects on anthropometrics, but it had no effects on physical activity and sedentary time. Fear of movement may be a salient determinant of sedentary time, which has to be further explored in this population. The results confirm sedentary being a construct necessary to separate from the lower end of a physical activity continuum and highlight the need of developing interventions targeting sedentary behaviours specifically.