https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71141-7.pdf

Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study

background Previous studies have suggested that the obstructive sleep apnea syndrome may be an important risk factor for stroke. It has not been determined, however, whether the syndrome is independently related to the risk of stroke or death from any cause after adjustment for other risk factors, including hypertension. methods In this observational cohort study, consecutive patients underwent polysomnography, and subsequent events (strokes and deaths) were verified. The diagnosis of the obstructive sleep apnea syndrome was based on an apnea–hypopnea index of 5 or higher (five or more events per hour); patients with an apnea–hypopnea index of less than 5 served as the comparison group. Proportional-hazards analysis was used to determine the independent effect of the obstructive sleep apnea syndrome on the composite outcome of stroke or death from any cause. results Among 1022 enrolled patients, 697 (68 percent) had the obstructive sleep apnea syndrome. At baseline, the mean apnea–hypopnea index in the patients with the syndrome was 35, as compared with a mean apnea–hypopnea index of 2 in the comparison group. In an unadjusted analysis, the obstructive sleep apnea syndrome was associated with stroke or death from any cause (hazard ratio, 2.24; 95 percent confidence interval, 1.30 to 3.86; P=0.004). After adjustment for age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, the obstructive sleep apnea syndrome retained a statistically significant association with stroke or death (hazard ratio, 1.97; 95 percent confidence interval, 1.12 to 3.48; P=0.01). In a trend analysis, increased severity of sleep apnea at baseline was associated with an increased risk of the development of the composite end point (P=0.005). conclusions The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa043104

Obstructive sleep apnea as a risk factor for stroke and death.

The prevalence and related clinical features of obstructive sleep apnea-hypopnea (OSAH) in the general population were estimated in a two-phase cross-sectional study. The first phase, completed by 2,148 subjects (76.9%), included a home survey, blood pressure, and a portable respiratory recording, whereas in the second, subjects with suspected OSAH (n = 442) and a subgroup of those with normal results (n = 305) were invited to undergo polysomnography (555 accepted). Habitual snoring was found in 35% of the population and breathing pauses in 6%. Both features occurred more frequently in men, showed a trend to increase with age, and were significantly associated with OSAH. Daytime hypersomnolence occurred in 18% of the subjects and was not associated with OSAH. An apnea-hypopnea index (AHI) > or = 10 was found in 19% of men and 15% of women. The prevalence of OSAH (AHI > or = 5) increased with age in both sexes, with an odds ratio (OR) of 2.2 for each 10-yr increase. AHI was associated with hypertension after adjusting for age, sex, body mass index, neck circumference, alcohol use, and smoking habit. This study adds evidence for a link between OSAH and hypertension.

https://www.atsjournals.org/doi/pdf/10.1164/ajrccm.163.3.2005065

Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr.

Background: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older. Methods and Findings: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: ,5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: $30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80– 1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleepdisordered breathing showed a pattern of association similar to all-cause mortality. Conclusions: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing. Please see later in the article for the Editors’ Summary.

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Sleep-disordered breathing and mortality: A prospective cohort study

The effects of age on the prevalence of sleep apnea in the general population remain unclear, because previous studies have focused on specific populations. The effects of age on the severity of apnea are unknown. This study was based on a two-stage general random sample of men (aged 20 to 100 yr), consisting of a telephone survey (n = 4,364) and a sleep laboratory evaluation of a survey subsample (n = 741). Obstructive sleep apnea (OSA), based on both sleep laboratory and clinical criteria (apnea/hypopnea index [AHI] > or = 10 and the presence of daytime symptoms) was found in 3.3% of the sample, with its maximum prevalence in the middle age group (45 to 64 yr). Also, based solely on laboratory criteria, the prevalence of OSA (obstructive AHI > or = 20) showed an age distribution similar to that of OSA diagnosed by laboratory and clinical criteria. The prevalence of any type of sleep apnea (central and obstructive) increased monotonically with age. However, central apnea appeared to account for this monotonic relationship with age. Severity of sleep apnea, as indicated by both number of events and minimum oxygen saturation, decreased with age when any sleep apnea criteria were used and when controlling for body mass index (BMI). The study shows that the prevalence of sleep apnea tends to increase with age but that the clinical significance (severity) of apnea decreases. On the basis of these findings, the sleep laboratory criteria used for diagnosis of sleep apnea should be adjusted for age.

Effects of age on sleep apnea in men: I. Prevalence and severity.

During 1976-1988 we diagnosed sleep apnea syndrome (SAS) in 1,620 adult men and women monitored in the Technion sleep laboratories. Their age at the time of diagnosis ranged between 21 and 79 years. Fifty-seven patients (53 men and 4 women) had died by 1990, 53% due to respiratory-cardiovascular causes. The observed/expected (O/E) mortality rates, calculated for men only, revealed excess mortality of patients under 70 years old. Excess mortality was significant in the fourth and fifth decades (3.33, p < 0.002; 3.23, p < 0.0002, respectively). In patients older than 70 O/E was 0.33 (p < 0.0007). Hierarchical multivariate analysis with four fixed variables [age, body mass index (BMI), hypertension and apnea index] and four additional variables added manually one at a time (heart disease, lung disease, diabetes, apnea duration) was used to determine the predictors of death from all causes, cardiopulmonary causes and from myocardial infarction (MI). All four major variables were found to be significant predictors of mortality from all causes, in addition to lung disease and heart disease. Only age and BMI were significant predictors of cardiopulmonary deaths in addition to lung disease. Age, BMI and hypertension predicted MI deaths in addition to lung disease. These results were interpreted to suggest that SAS affects death indirectly, most probably by being a risk factor for hypertension.

Mortality in Sleep Apnea Patients: A Multivariate Analysis of Risk Factors

Periodic leg movements in sleep were diagnosed in 8 patients with insomnia and in 12 patients with hypersomnia. Polysom-nography did not reveal any difference in the number of leg movements in these groups, the mean duration of a leg movement, or the number of activity epochs. Those with insomnia, however, had a shorter intermovement interval than those with hypersomnia, with more leg movements in each activity epoch. Treatment with 0.5 to 2 mg clonazepam improved subjective complaints and decreased the number of leg movements without affecting the intermovement interval or movement duration.

Periodic leg movements in sleep: effect of clonazepam treatment.

Ultrashort sleep-waking schedule. II. Relationship between ultradian rhythms in sleepability and the REM-non-REM cycles and effects of the circadian phase.

Systematic trends in the length of apneas were investigated in 8 sleep apnea patients, all of whom had more than 200 apneas per night. Regression analysis performed on the length of apneas by thirds of the night revealed significant linear trends for apneas in sleep stage 2, and for apneas in all sleep stages pooled together. There were no significant trends in the index of apnea density. We suggest that the across-night lengthening of apneas reflects a progressive increase in the arousal threshold, either by a compensatory deepening of sleep or by progressive changes in respiratory chemoreceptor sensitivity. The lack of significant trends in rapid eye movement (REM) sleep supports the conclusion that apnea termination in REM sleep is mediated by a different mechanism than in non-REM sleep.

/pdf/across-night-lengthening-of-sleep-apneic-episodes-28wtw5qjc8.pdf

Across-night lengthening of sleep apneic episodes.

Twenty-five adults with a deviated nasal septum, who complained about excessive daytime sleepiness, chronic fatigue, and nocturnal insomnia, were studied for one to two nights in a sleep laboratory. Recordings disclosed disordered breathing during sleep in the form of pronounced periodic breathing of alternating hypopneas and hyperpneas, isolated hypopneic episodes and central apneas and periodic sighs, all combined with electrophysiologic "microarousals," and a mixture of alpha and delta EEG wave activities. Surgical treatment of the deviated septum in 14 patients resulted in a subjective improvement in the level of diurnal alertness and in the quality of nocturnal sleep in 12 patients. Follow-up sleep recordings in seven of the patients who reported subjective improvement in sleep disclosed notably less waking and abnormal breathing during sleep. These results suggest that increased upper airway resistance can cause nonapneic breathing disorders in sleep and, consequently, sleep disturbances.

Jacob Zomer

Papers

Mortality in Sleep Apnea Patients: A Multivariate Analysis of Risk Factors

Periodic leg movements in sleep: effect of clonazepam treatment.

Ultrashort sleep-waking schedule. II. Relationship between ultradian rhythms in sleepability and the REM-non-REM cycles and effects of the circadian phase.

Across-night lengthening of sleep apneic episodes.

Excessive daytime sleepiness and insomnia.