Sleep related breathing disorders in older men: A search for underlying mechanisms

—The incidence of sleep-related breathing disorders (SRBDs) associated with hemoglobin desaturation was determined by nocturnal polygraphic evaluations in 26 healthy men, aged 55–70 years. Sixteen subjects (62%) had abnormal rates of at least 12 episodes per hour of sleep: 8 had occlusive, and 8 had central apnea or hypopnea. During waking ten of 16 SRBD subjects and only one subject without SRBDs exhibited either an elevated nasopharyngeal airway resistance (n=4) or a reduced ventilatory response to hypercapnia (n=4) and/or hypoxia (n=3). However, these abnormalities were not related to the type or severity of SRBDs, and 6 subjects with SRBDs demonstrated no respiratory defect. We conclude that SRBDs have a very high incidence in older males and are not usually secondary to pulmonary cardiac, neurological, or behavioral disorders. Additionally, we hypothesize that abnormalities in ventilatory control or upper airway resistance contribute to SRBDs, but depression of brain stem reticular formation activity during sleep plays a primary role in these disorders. Factors related to both aging and SRBDs are reviewed. These include reduced chemoreceptor responses, altered steroid hormone metabolism, and use and metabolism of hypnotic drugs and alcohol.     

Complex sleep apnea and obesity hypoventilation syndrome. Opposite ends of the spectrum of obstructive sleep apnea?

In most cases, the application of continuous positive airway pressure (CPAP) during sleep in patients affected by obstructive sleep apnea (OSA) eliminates upper airway obstruction and makes breathing stable and regular. However, some OSA patients develop periodic breathing and central apneas during CPAP administration, a finding that has been labelled as “complex sleep apnea” (complex SA). Such breathing disorder may occur only acutely after CPAP treatment initiation or sometimes persist with chronic CPAP treatment. We hypothesize that complex SA may be the consequence of mechanisms analogous to those leading to obesity hypoventilation syndrome (OHS), but operating in an opposite direction.Periodic breathing is one of the factors predisposing to OSA and is an essential factor for the recurrence of central apneas in normo or hypocapnic patients. A high ventilatory responsiveness to chemical stimuli enhances breathing periodicity. In subjects with periodic central apneas chemoresponsiveness is high, while in subjects with OSA it spans throughout a wide range, and is correlated to diurnal blood gas levels. In fact, sleep respiratory disorders may be responsible for either an augmentation in ventilatory responses to chemical stimuli consequent to chronic exposure to intermittent hypoxia, or for a decrease in ventilatory responses when prolonged exposure to hypercapnia is experienced. Among OSA subjects, those with OHS show very depressed hypercapnic responses. After chronic OSA treatment, ventilatory responses to chemical stimuli may either decrease, in previously hyperresponsive subjects, or increase, in previously hyporesponsive subjects. Most patients with OHS decrease daytime PCO₂ levels and increase their ventilatory responses after chronic CPAP treatment.Complex SA could appear in those OSA subjects in whom chronic exposure to nocturnal respiratory disorders leads to the highest responsiveness to chemical stimuli, and could disappear after blunting of ventilatory responses following chronic CPAP treatment. Complex SA may be one extreme of evolutionary spectrum of OSA, the opposite end being represented by OHS.     

Effect of high-fat diet and metformin treatment on ventilation and sleep apnea in non-obese rats

We investigated the effect of insulin resistance on ventilation and the incidence of sleep apnea in non-obese rats and determined whether metformin could change ventilation and occurrence of sleep apneas. Five groups of rats were studied: (1) standard chow; (2) high-fat groups, with 1 with metformin; (2) had type 2 diabetes induced by streptozotocin, with 1 with metformin. Compared to standard rats, ventilatory parameters remained unchanged in the high-fat fed diet as well as in diabetic rats. However, their oxygen consumption was reduced (p相似文献   

Correlations among Epworth Sleepiness Scale scores, multiple sleep latency tests and psychological symptoms

The aim of this study was to identify factors other than objective sleep tendency associated with scores on the Epworth Sleepiness Scale (ESS). There were 225 subjects, of whom 40% had obstructive sleep apnoea (OSA), 16% had simple snoring, and 4.9% had snoring with sleep disruption (upper airway resistance syndrome); 9.3% had narcolepsy and 7.5% had hypersomnolence without REM sleep abnormalities; 12% had chronic fatigue syndrome; 7.5% had periodic limb movement disorder and 3% had diurnal rhythm disorders. ESS, the results of overnight polysomnography and multiple sleep latency test (MSLT) and SCL-90 as a measure of psychological symptoms were recorded. The ESS score and the mean sleep latency (MSL) were correlated (Spearman ö =−0.30, P <0.0001). The MSL was correlated with total sleep time (TST) and with sleep efficiency but not with apnoea/hypopnoea index. There was no association between the MSL and any aspect of SCL-90 scores, except a borderline significant association with the somatisation subscale. The ESS was correlated with TST but not with sleep efficiency or apnoea/hypopnoea index. The ESS was correlated with all subscales of the SCL-90 except psychoticism. An ESS≥10 had poor sensitivity and specificity as a predictor of MSL <10 min or MSL <5 min. We conclude that the MSLT and the ESS are not interchangeable. The ESS was influenced by psychological factors by which the MSL was not affected. The ESS cannot be used to demonstrate or exclude sleepiness as it is measured by MSLT.     

Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study

SUBJECT OBJECTIVE: This study further evaluated the effects of tiagabine on sleep in elderly subjects with primary insomnia. METHODS: Elderly subjects (aged 65-85 years) meeting DSM-IV-TR criteria for primary insomnia were randomly assigned to receive tiagabine 2, 4, 6, or 8 mg or placebo on 2 consecutive nights. Efficacy was assessed using standard polysomnography and a postsleep questionnaire. Additional assessments included the Assessment of Daily Functioning, Digit Symbol Substitution Test (for residual effects), and visual analog scale (for sleepiness/alertness). RESULTS: A total of 207 subjects were randomly assigned to study medication (tiagabine: 2 mg, n = 43; 4 mg, n = 38; 6 mg, n = 45; 8 mg, n = 43; placebo, n = 38). Tiagabine did not significantly effect wake after sleep onset, latency to persistent sleep, or total sleep time compared with placebo (P > .05). Significant increases in Stage 3+4 sleep (i.e., slow-wave sleep) were found for tiagabine 4, 6, and 8 mg versus placebo, with a corresponding significant decrease in Stage 1 sleep (P < .05). At 6 and 8 mg, tiagabine also significantly reduced the number of awakenings and increased the ratio of Stage 3+4/(Stage 1 +wake after sleep onset). In general, there were no significant effects on subjects' ratings of sleep or daily functioning with tiagabine 2, 4, and 6 mg versus placebo. These 3 doses had tolerability profiles comparable with that of placebo and were not associated with significant residual effects or reduced alertness. The 8-mg dose, however, significantly decreased subjective total sleep time and refreshing quality of sleep, as well as daily functioning. This dose was associated with troublesome adverse events, significant residual effects, and reduced alertness. CONCLUSIONS: In elderly subjects with primary insomnia, tiagabine did not have a significant effect on wake after sleep onset, latency to persistent sleep, total sleep time, or the subjective rating of sleep. Tiagabine 4, 6, and 8 mg significantly increased slow-wave sleep, with a corresponding significant decrease in Stage 1 sleep. Tiagabine was generally well tolerated, with doses of less than 6 mg having tolerability profiles generally similar to that of placebo. The 8-mg dose, however, was associated with troublesome adverse events, residual effects, and reduced alertness.     

Differential Expression of Lipid and Carbohydrate Metabolism Genes in Upper Airway versus Diaphragm Muscle

Study Objectives:

Contractile properties of upper airway muscles influence upper airway patency, an issue of particular importance for subjects with obstructive sleep apnea. Expression of genes related to cellular energetics is, in turn, critical for the maintenance of contractile integrity over time during repetitive activation. We tested the hypothesis that sternohyoid has lower expression of genes related to lipid and carbohydrate energetic pathways than the diaphragm.

Methods:

Sternohyoid and diaphragm from normal adult rats were examined with gene expression arrays. Analysis focused on genes belonging to Gene Ontology (GO) groups carbohydrate metabolism and lipid metabolism.

Results:

There were 433 genes with at least ± 2-fold significant differential expression between sternohyoid and diaphragm, of which 192 had sternohyoid > diaphragm and 241 had diaphragm > sternohyoid expression. Among genes with higher sternohyoid expression, there was over-representation of the GO group carbohydrate metabolism (P = 0.0053, n = 13 genes, range of differential expression 2.1- to 6.2-fold) but not lipid metabolism (P = 0.44). Conversely, among genes with higher diaphragm expression, there was over-representation of the GO group lipid metabolism (P = 0.0000065, n = 32 genes, range of differential expression 2.0- to 37.9-fold) but not carbohydrate metabolism (P = 0.23). Nineteen genes with diaphragm > sternohyoid expression were related to fatty acid metabolism (P = 0.000000058), in particular fatty acid β oxidation and biosynthesis in the mitochondria.

Conclusions:

Sternohyoid has much lower gene expression than diaphragm for mitochondrial enzymes that participate in fatty acid oxidation and biosynthesis. This likely contributes to the lower fatigue resistance of pharyngeal upper airway muscles compared with the diaphragm.

Citation:

van Lunteren E; Spiegler S; Moyer M. Differential expression of lipid and carbohydrate metabolism genes in upper airway versus diaphragm muscle. SLEEP 2010;33(3):363-370.     

Neurochemical perspectives on the control of breathing during sleep

A specific depression of minute ventilation occurs during sleep in normal subjects. This sleep-related ventilatory depression is partially related to mechanical events and upper airway atonia but some data also indicate that it is likely to be centrally mediated. This paper reviews the anatomical and neurochemical connections between sleep/wake- and respiratory-related areas in an attempt to identify the potential implication of sleep-related neurochemicals (serotonin, catecholamines, GABA, acetylcholine) in the sleep-related hypoventilation. The review of available data suggests that the sleep-related ventilatory depression depends upon the enhanced GABAergic activity together with a loss of suprapontine influence depending on the cessation of activity of the reticular formation. During REM sleep, an additional inhibitory activity emerges from the pontine cholinergic neurons, which contributes to the breathing irregularities and the associated depression of minute ventilation and ventilatory response to chemical stimuli. This model may contribute to a better understanding of the neurochemical environment of respiratory neurons during sleep, which remains a question of importance regarding the numerous pathological states that are linked to specific perturbations of breathing control during sleep.     

Puberty and upper airway dynamics during sleep

STUDY OBJECTIVES: The upper airway compensatory response to subatmospheric pressure loading declines with age. The epidemiology of obstructive sleep apnea suggests that sex hormones play a role in modulating upper airway function. Sex hormones increase gradually during puberty, from minimally detectable to adult levels. We hypothesized that the upper airway response to subatmospheric pressure loading decreased with increasing pubertal Tanner stage in males but remained stable during puberty in females. DESIGN: Upper airway dynamic function during sleep was measured over the course of puberty. PARTICIPANTS: Normal subjects of Tanner stages 1 to 5. MEASUREMENTS: During sleep, maximal inspiratory airflow was measured while varying the level of nasal pressure. The slope of the upstream pressure-flow relationship (SPF) was measured. RESULTS: The SPF correlated with age and Tanner stage. However, the relationship with Tanner stage became nonsignificant when the correlation due to the mutual association with age was removed. Females had a lower SPF than males. CONCLUSIONS: In both sexes, the upper airway compensatory response to subatmospheric pressure loading decreased with age rather than degree of pubertal development. Thus, changes in sex hormones are unlikely to be a primary modulator of upper airway function during the transition from childhood to adulthood. Although further studies of upper airway structural changes during puberty are needed, we speculate that the changes in upper airway function with age are due to the depressant effect of age on ventilatory drive, leading to a decrease in upper airway neuromotor tone.     

Aerobic exercise affects sleep,psychological wellbeing and immune system parameters among subjects with chronic primary insomnia

BackgroundChronic primary insomnia is characterized by long-term difficulties in maintaining and initiating sleep, too early waking up, poor mood, fatigue, impaired concentration and poor quality of life. Exercise training is recommended to prevent and alleviate sleep disorders.ObjectiveThe aim of the study was to investigate the influence of aerobic exercise training on quality of sleep, psychological wellbeing and immune system among subjects with chronic primary insomnia.Material and methodsEighty previously sedentary subjects with chronic primary insomnia subjects enrolled in this study, their age ranged from 35–56 years. All participants were randomly assigned to supervised aerobic exercise intervention group (group A, n=40) or control group (group B, n=40). Polysomnographic recordings for sleep quality assessment, Beck Depression Inventory (BDI), Profile of Mood States(POMS), Rosenberg Self-Esteem Scale (RSES), number of CD3+, CD4+, CD8+ T cells count and CD4/CD8 ratio were measured before and at the end of the study after six months.ResultsThere was a significant increase in the total sleep duration, sleep efficiency and sleep onset latency in group(A) after six months of aerobic exercise training, while, wake time after sleep onset and rapid eye movement (REM) latency significantly reduced after six months of aerobic training compared with values obtained prior to aerobic exercise training. Also, the mean values of BDI, POMS, CD3 count, CD4 count and CD8 count decreased significantly and the mean value of RSES significantly increased in group (A) after the aerobic exercise training, while the results of the control group were not significant. Moreover, there were significant differences between both groups at the end of the study.ConclusionExercise training can be considered as a non-pharmacological modalty for modifying sleep quality, psychological wellbeing and immune system among subjects with chronic primary insomnia.     

Treatment of obstructive sleep apnea in achondroplasia: Evaluation of sleep,breathing, and somatosensory-evoked potentials

The occurrence of obstructive sleep apnea (OSA) in achondroplasia has been linked to brain stem compression. Overnight sleep studies (11 subjects) and somatosensoryevoked potentials (SEP's, 10 subjects) were recorded before and after conventional treatment of OSA in achondroplasia. The two groups were derived from 30 subjects who underwent diagnostic sleep studies and SEPs, including 15 females and 15 males with a median age 6.6 of years (range 1.0–47.6) at the time of the first study. In 30 initial studies there was no correlation between severity of OSA and abnormalities on SEP evaluation. Treatment of 17 subjects included adenotonsillectomy (n = 3), weight loss (n = 1), and nasal-mask continuous positive airway pressure (CPAP) (n = 13). Sleep studies in 11 subjects after a delay of 8.8 ± 2.8 months showed a reduction in respiratory disturbance index (RDI) from 38.4 ± 6.9 to 6.5 ± 1.8 events hr^?1 (p < 0.001) and movements/arousals fell from 10.4 ± 2.2 to 4.8 ± 0.2 hr^?1 (p < 0.04). Obstructive events were reduced from 33.7 ± 6.9 to 2.4 ± 1.0 hr^?1 (p < 0.001). Improvement of respiratory indices was associated with an increased proportion of slow-wave sleep from 25.2 ± 4.0% to 32.3 ± 2.4% (p = 0.01), and decrease in stage 1–2 sleep from 59.3 ± 5.8% to 46.6 ± 1.9% (p = 0.03). There was no increase in the percentage of REM sleep (15.2% to 21.2%). Repeat SEP studies in 10 subjects, after clinically effective treatment of OSA, showed improvement of SEP score of at least 1 grade, in 5 of 7 (71%) with initially abnormal values. We conclude that treatment to relieve upper airway obstruction improves OSA in achondroplasia, accompanied by changes in sleep structure and, in some cases, improved studies of neurological function. © 1995 Wiley-Liss, Inc.