The multifaceted aspects of sleep and sleep-wake disorders following stroke.

Sleep-wake disorders (SWD) are acknowledged risk factors for both ischemic stroke and poor cardiovascular and functional outcome after stroke. SWD are frequent following stroke, with sleep apnea (SA) being the most frequent SWD affecting more than half of stroke survivors. While sleep disturbances and SWD are frequently reported in the acute phase, they may persist in the chronic phase after an ischemic stroke. Despite the frequency and risk associated with SWD following stroke, screening for SWD remains rare in the clinical setting, due to challenges in the assessment of post-stroke SWD, uncertainty regarding the optimal timing for their diagnosis, and a lack of clear treatment guidelines (i.e., when to treat and the optimal treatment strategy). However, little evidence support the feasibility of SWD treatment even in the acute phase of stroke and its favorable effect on long-term cardiovascular and functional outcomes. Thus, sleep health recommendations and SWD treatment should be systematically embedded in secondary stroke prevention strategy. We therefore propose that the management of SWD associated with stroke should rely on a multidisciplinary approach, with an integrated diagnostic, treatment, and follow-up strategy. The challenges in the field are to improve post-stroke SWD diagnosis, prognosis and treatment, through a better appraisal of their pathophysiology and temporal evolution.

Self-reported sleepiness and not the apnoea hypopnoea index is the best predictor of sleepiness-related accidents in obstructive sleep apnoea.

To evaluate the value of apnoea + hypopnoea index versus self-reported sleepiness at the wheel in anticipating the risk of sleepiness-related accidents in patients referred for obstructive sleep apnoea. A cross-sectional analysis of the French national obstructive sleep apnoea registry. 58,815 subjects referred for a suspicion of obstructive sleep apnoea were investigated by specific items addressing sleepiness at the wheel and sleepiness-related accidents. Apnoea + hypopnoea index was evaluated with a respiratory polygraphy or full polysomnography. Subjects had a median age of 55.6 years [45.3; 64.6], 65% were men, with a median apnoea + hypopnoea index of 22 [8; 39] events/h. Median Epworth sleepiness scale score was 9 [6; 13], 35% of the patients reported sleepiness at the wheel (n = 20,310), 8% (n = 4,588) reported a near-miss accident and 2% (n = 1,313) reported a sleepiness-related accident. Patients reporting sleepiness at the wheel whatever their obstructive sleep apnoea status and severity exhibited a tenfold higher risk of sleepiness-related accidents. In multivariate analysis, other predictors for sleepiness-related accidents were: male gender, ESS, history of previous near-miss accidents, restless leg syndrome/periodic leg movements, complaints of memory dysfunction and nocturnal sweating. Sleep apnoea per se was not an independent contributor. Self-reported sleepiness at the wheel is a better predictor of sleepiness-related traffic accidents than apnoea + hypopnoea index.

[Telemonitoring in continuous positive airway pressure-treated patients with obstructive sleep apnoea syndrome: An algorithm proposal]. / Télésuivi des patients traités par pression positive continue pour un syndrome d'apnées/hypopnées obstructives du sommeil : proposition d'un arbre décisionnel.

Most of the continuous positive airway pressure (CPAP) devices currently in use allow telemonitoring of observance, leaks and the apnoea-hypopnoea index (AHI). La Société française de recherche et de médecine du sommeil (SFRMS) and La Société de pneumologie de langue française (SPLF) workgroup offer to CPAP prescribers and to home care providers a scientific document which has the following purposes: to underline the relevance of the telemonitoring of leaks and the AHI, to define alert thresholds, to describe the principal mechanisms generating excessive leaks and high AHI, and to propose a diagnostic algorithm.

[Cardiac dysfunction and the obstructive sleep apnoea syndrome]. / Dysfonction cardiaque et syndrome d'apnée du sommeil.

INTRODUCTION: Cardiac insufficiency affects nearly 2% of the population with increased morbidity/mortality despite advances in therapeutic management. The sleep apnoea syndrome (SAS) is a risk factor for, and cause of aggravation of, myocardial dysfunction. BACKGROUND: SAS is found in 70% of patients with chronic cardiac failure, 65% of patients with refractory hypertension, 60% of patients with cerebro-vascular accidents and 50% of patients with atrial fibrillation. The associated cardiovascular mortality is multiplied by a factor of 2 to 3. The pathophysiological mechanisms are intermittent nocturnal hypoxia, variations in CO2 levels, variations in intrathoracic pressure and repeated arrousals from sleep, concurrent with sympathetic hyperactivity, endothelial dysfunction and systemic inflammation. CONCLUSIONS: SAS and cardiological management in patients presenting with myocardial dysfunction should be combined. It is necessary to pursue the scientific investigations with the aim of determining a precise care pathway and the respective places of each of the cardiological and pulmonary measures.

Obstructive sleep apnoea syndrome in patients living with diabetes: Which patients should be screened?

AIM: Because type 2 diabetes (T2D) is related to obesity, it is often associated with obstructive sleep apnoea syndrome (OSAS), although OSAS is also frequently diagnosed in patients with type 1 diabetes (T1D) and may promote gestational diabetes. Thus, this systematic review of the scientific evidence aimed to evaluate the epidemiological association between OSAS and all forms of diabetes, the current understanding of the pathophysiological mechanisms behind these associations, the expected benefits and limitations of OSAS treatment in patients with diabetes and, finally, to propose which patients require screening for OSAS. METHODS: A panel comprising French expert endocrinologists and pneumologists was convened. Two of these experts made a search of the relevant literature for each subpart of the present report; all panel experts then critically reviewed the entire report separately as well as collectively. RESULTS: There is little evidence to support the notion that OSAS treatment improves glycated haemoglobin, although it may improve nighttime blood glucose control and insulin sensitivity. However, there is robust evidence that OSAS treatment lowers 24-h blood pressure. CONCLUSION: The high prevalence of OSAS in patients with T1D and T2D justifies screening for the syndrome, which should be based on clinical symptoms, as the benefits of OSAS treatment are mainly improvement of symptoms related to sleep apnoea. There are also several clinical situations wherein screening for OSAS seems justified in patients with diabetes even when they have no symptoms, particularly to optimalize control of blood pressure in cases of resistant hypertension and microvascular complications.

Fixed-pressure CPAP versus auto-adjusting CPAP: comparison of efficacy on blood pressure in obstructive sleep apnoea, a randomised clinical trial.

BACKGROUND: Millions of individuals with obstructive sleep apnoea (OSA) are treated by CPAP aimed at reducing blood pressure (BP) and thus cardiovascular risk. However, evidence is scarce concerning the impact of different CPAP modalities on BP evolution. METHODS: This double-blind, randomised clinical trial of parallel groups of patients with OSA indicated for CPAP treatment compared the efficacy of fixed-pressure CPAP (FP-CPAP) with auto-adjusting CPAP (AutoCPAP) in reducing BP. The primary endpoint was the change in office systolic BP after 4 months. Secondary endpoints included 24 h BP measurements. RESULTS: Patients (322) were randomised to FP-CPAP (n=161) or AutoCPAP (n=161). The mean apnoea+hypopnoea index (AHI) was 43/h (SD, 21); mean age was 57 (SD, 11), with 70% of males; mean body mass index was 31.3 kg/m(2) (SD, 6.6) and median device use was 5.1 h/night. In the intention-to-treat analysis, office systolic blood pressure decreased by 2.2 mm Hg (95% CI -5.8 to 1.4) and 0.4 mm Hg (-4.3 to 3.4) in the FP-CPAP and AutoCPAP group, respectively (group difference: -1.3 mm Hg (95% CI -4.1 to 1.5); p=0.37, adjusted for baseline BP values). 24 h diastolic BP (DBP) decreased by 1.7 mm Hg (95% CI -3.9 to 0.5) and 0.5 mm Hg (95% CI -2.3 to 1.3) in the FP-CPAP and AutoCPAP group, respectively (group difference: -1.4 mm Hg (95% CI -2.7 to -0.01); p=0.048, adjusted for baseline BP values). CONCLUSIONS: The result was negative regarding the primary outcome of office BP, while FP-CPAP was more effective in reducing 24 h DBP (a secondary outcome). TRIAL REGISTRATION NUMBER: NCT01090297.

Glucose tolerance and cardiovascular risk biomarkers in non-diabetic non-obese obstructive sleep apnea patients: Effects of long-term continuous positive airway pressure.

BACKGROUND: Insulin resistance, glucose dyshomeostasis and oxidative stress are associated to the cardiovascular consequences of obstructive sleep apnea (OSA). The effects of a long-term continuous positive airway pressure (LT-CPAP) treatment on such mechanisms still remain conflicting. OBJECTIVE: To investigate the effect of LT-CPAP on glucose tolerance, insulin sensitivity, oxidative stress and cardiovascular biomarkers in non-obese non-diabetic OSA patients. PATIENTS & METHODS: Twenty-eight apneic, otherwise healthy, men suffering from OSA (mean age = 48.9 ± 9.4 years; apnea-hypopnea index = 41.1 ± 16.1 events/h; BMI = 26.6 ± 2.8 kg/m(2); fasting glucose = 4.98 ± 0.37 mmol/L) were evaluated before and after LT-CPAP by an oral glucose tolerance test (OGTT), measuring plasma glucose, insulin and proinsulin. Glycated hemoglobin, homeostasis model assessment resistance insulin, blood lipids, oxidative stress, homocysteine and NT-pro-brain natriuretic peptide (NT-proBNP) were also measured. RESULTS: LT-CPAP treatment lasted 13.9 ± 6.5 months. At baseline, the time spent at SaO2<90%, minimal and mean SaO2 were associated with insulin area under the curve during OGTT (r = 0.448, P = 0.011; r = -0.382; P = 0.047 and r = -0.424; P = 0.028, respectively) and most other glucose/insulin homeostasis biomarkers, as well as with homocysteine (r = 0.531, P = 0.006; r = -0.487; P = 0.011 and r = -0.409; P = 0.034, respectively). LT-CPAP had no effect on all the OGTT-related measurements, but increased plasma total antioxidant status (+7.74%; P = 0.035) in a duration-dependent manner (r = 0.607; P < 0.001), and decreased both homocysteine (-15.2%; P = 0.002) and NT-proBNP levels (-39.3%; P = 0.002). CONCLUSIONS: In non-obese non-diabetic OSA patients, nocturnal oxygen desaturation is strongly associated to insulin resistance. LT-CPAP does not improve glucose homeostasis nor insulin sensitivity but has a favorable effect on antioxidant capacity and cardiovascular risk biomarkers.

Adaptive servo-ventilation: How does it fit into the treatment of central sleep apnoea syndrome? Expert opinions.

The preliminary results of the SERVE-HF study have led to the release of safety information with subsequent contraindication to the use of adaptive servo-ventilation (ASV) for the treatment of central sleep apnoeas in patients with chronic symptomatic systolic heart failure with left ventricular ejection fraction (LVEF) ≤ 45%. The aim of this article is to review these results, and to provide more detailed arguments based on data from the literature advocating the continued use of ASV in different indications, including heart failure with preserved LVEF, complex sleep apnoea syndrome, opioid-induced central sleep apnea syndrome, idiopathic central SAS, and central SAS due to a stroke. Based on these findings, we propose to set up registers dedicated to patients in whom ASV has been stopped and in the context of the next setting up of ASV in these specific indications to ensure patient safety and allow reasoned decisions on the use of ASV.

[Cardiovascular morbidity associated with obstructive sleep apnea syndrome]. / Morbidité cardiovasculaire associée au syndrome d'apnée obstructive du sommeil.

INTRODUCTION: The obstructive sleep apnoea syndrome (OSAS) had become a major public health concern in modern society due to its high prevalence but, above all, to its associated morbidity, especially cardiovascular. BACKGROUND: Untreated OSAS is associated with an increased incidence of fatal (myocardial infarction and stroke) (odds ratio: 2.87) and non-fatal cardiovascular events (myocardial infarction, stroke, coronary artery bypass surgery and coronary angiography) (odds ratio: 3.17). Moreover, the prevalence of hypertension in patients with OSAS is high, between 35 and 80%. The pathophysiological mechanisms leading to these complications are mainly due to intermittent hypoxia secondary to repeated episodes of apnoea/hypopnoea during sleep. These mechanisms include sympathetic hyperactivation, impairment of vasomotor reactivity, vascular inflammation, oxidative stress and metabolic disorders. In patients with OSAS, the impact of continuous positive pressure is proven in terms of prevention of cardiovascular events although blood pressure reduction is limited. Obviously these effects are proportional to observance. CONCLUSION: OSAS does increase the cardiovascular risk, independently of other risk factors. Although the impact of treatment is relatively low in decreasing blood pressure, it seems essentially effective in preventing cardiovascular morbidity. Therefore, OSAS screening, and the association of specific treatments in cardio-metabolic patients and OSAS patients respectively, should be included in clinical strategies.

Sympathetic overactivity due to sleep fragmentation is associated with elevated diurnal systolic blood pressure in healthy elderly subjects: the PROOF-SYNAPSE study.

AIMS: Sleep fragmentation is a landmark of sleep disorders, because microarousals are systematically associated with sympathetic surges (i.e., sympathetic arousals). However, the impact of sympathetic sleep fragmentation on blood pressure (BP) remains understudied. We assessed the relationships between 24 h ambulatory BP monitoring, the autonomic arousal index (AAI) derived from pulse transit time, and heart rate variability indices. We hypothesized that repeated sympathetic arousals during sleep are associated with elevated BP in a large population of elderly volunteers. METHODS AND RESULTS: Volunteer subjects (n = 780, 57.4% women) with a mean age of 68.7 years and free of known sleep-disordered breathing, coronary heart diseases, and neurological disorders underwent polygraphy, 24 h ECG Holter monitoring, and 24 h ambulatory BP monitoring. Multivariate regressions showed that sleep fragmentation, expressed by AAI, was associated with elevated diurnal (P = 0.008) and 24 h (P = 0.005) systolic BP and higher risk for 24 h [odds ratio (OR): 1.70 (1.04-2.80), P = 0.036] systolic hypertension, independently of confounders such as sleep-disordered breathing, body mass index, sex, diabetes, hypercholesterolaemia, and self-reported sleep duration and quality. Increased AAI was associated with higher nocturnal and diurnal low-frequency power (P < 0.001) and low-to-high-frequency ratio (P < 0.001), suggesting nocturnal and diurnal sympathetic overactivity. CONCLUSION: In healthy elderly subjects, repetitive sympathetic arousals during sleep are associated with elevated systolic BP and higher risk of hypertension, after controlling for confounders. Sympathetic overactivity is the proposed underlying mechanism. CLINICAL TRIAL REGISTRATION: NCT00766584 and NCT00759304.

The upper airway resistance syndrome.

Obstructive sleep apnea syndrome has been recognized as a major public health problem. Both its cardiovascular and metabolic comorbidities and symptoms motivate for an accurate diagnosis and appropriate treatment. The main stimulus associated with obstructive sleep apnea (OSA) and explaining deleterious consequences is intermittent hypoxia. The upper airway resistance syndrome (UARS) has been described based on the hypothesis that snoring and repetitive occurrence of respiratory effort-related arousals (RERAs) but not oxygen desaturation might produce a significant disease with symptoms, altered quality of life and cardiovascular morbidity. Diurnal sleepiness remains the main diagnostic criteria, which is often confounded with tiredness in women. UARS patients may also report insomnia and symptoms that closely resemble those of the functional somatic syndromes. Currently, the International Classification of Sleep Disorders does not individualize UARS as a specific entity and reports UARS patients as a subgroup of OSA. However, RERAs are described as unambiguous abnormal respiratory events occurring during sleep and requiring a specific scoring. In this review, the authors attempt to describe the specific characteristics of UARS that are relevant for both clinicians and researchers.

The impact of obstructive sleep apnea on homocysteine and carotid remodeling in metabolic syndrome.

Obstructive sleep apnea (OSA) and metabolic syndrome (MetS) are associated with increased cardiovascular morbidity and mortality. Increased homocysteine is suggested as an independent risk factor for atherosclerosis and cardiovascular disease but remains disputed in OSA. We assessed polysomnography, carotid intima-media thickness (CIMT) and biology in 35 MetS patients, according to the presence (OSA+MetS; n=26) or the absence of OSA (MetS; n=9). In OSA+MetS patients, homocysteine levels were increased compared to MetS subjects (12.8 ± 3.8 vs. 9.5 ± 2.5 µmol/L; P=0.026). In the whole population, homocysteine correlated with apnea-hypopnea index (AHI) (r=0.522; P=0.001) and CIMT (r=0.376; P=0.026). Homocysteine was negatively correlated with plasma thiols (r=-0.406; P=0.017) and positively with urinary 15-F2t-isoprostanes (r=0.347; P=0.044). Multivariate regression analysis revealed that AHI (ß=0.559; P<0.001) and urinary 15-F2t-isoprostane (ß=0.310; P=0.018) were independently associated with homocysteine level. We conclude that homocysteine level was higher in MetS when associated with OSA and proportional to OSA severity. In this context, vascular remodeling appeared more severe and mediated by oxidative stress.

14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans.

Obstructive sleep apnoea syndrome (OSAS) causes nocturnal chronic intermittent hypoxia (IH) that contributes to excess cardiovascular morbidity. To explore the consequences of IH, we used our recently developed model of nocturnal IH in healthy humans to characterise the profile of this blood pressure increase, to determine if it is sustained and to explore potential physiological mechanisms. We performed 24-h ambulatory monitoring of blood pressure in 12 healthy subjects before and after 2 weeks of IH exposure. We also assessed systemic haemodynamics, muscle sympathetic nerve activity (MSNA), ischaemic calf blood flow responses and baroreflex gain. We obtained blood samples for inflammatory markers before, during and after exposure. IH significantly increased daytime ambulatory blood pressure after a single night of exposure (3 mmHg for mean and diastolic) and further increased daytime pressures after 2 weeks of exposure (8 mmHg systolic and 5 mmHg diastolic). Mean ± sd MSNA increased across the exposure (17.2 ± 5.1 versus 21.7 ± 7.3 bursts·min⁻¹; p < 0.01) and baroreflex control of sympathetic outflow declined from -965.3 ± 375.1 to -598.4 ± 162.6 AIU·min⁻¹ ·mmHg⁻¹ (p < 0.01). There were no evident changes in either vascular reactivity or systemic inflammatory markers. These data are the first to show that the arterial pressure rise is sustained throughout the waking hours beyond the acute phase immediately after exposure. Moreover, they may suggest that sympathoactivation induced by IH likely contributes to blood pressure elevation and may derive from reduced baroreflex inhibition. These mechanisms may reflect those underlying the blood pressure elevation associated with OSAS.

Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity.

Chronic intermittent hypoxia (CIH) is thought to be responsible for the cardiovascular disease associated with obstructive sleep apnea (OSA). Increased sympathetic activation, altered vascular function, and inflammation are all putative mechanisms. We recently reported (Tamisier R, Gilmartin GS, Launois SH, Pepin JL, Nespoulet H, Thomas RJ, Levy P, Weiss JW. J Appl Physiol 107: 17-24, 2009) a new model of CIH in healthy humans that is associated with both increases in blood pressure and augmented peripheral chemosensitivity. We tested the hypothesis that exposure to CIH would also result in augmented muscle sympathetic nerve activity (MSNA) and altered vascular reactivity contributing to blood pressure elevation. We therefore exposed healthy subjects between the ages of 20 and 34 yr (n = 7) to 9 h of nocturnal intermittent hypoxia for 28 consecutive nights. Cardiovascular and hemodynamic variables were recorded at three time points; MSNA was collected before and after exposure. Diastolic blood pressure (71 +/- 1.3 vs. 74 +/- 1.7 mmHg, P < 0.01), MSNA [9.94 +/- 2.0 to 14.63 +/- 1.5 bursts/min (P < 0.05); 16.89 +/- 3.2 to 26.97 +/- 3.3 bursts/100 heartbeats (hb) (P = 0.01)], and forearm vascular resistance (FVR) (35.3 +/- 5.8 vs. 55.3 +/- 6.5 mmHg x ml(-1) x min x 100 g tissue, P = 0.01) all increased significantly after 4 wk of exposure. Forearm blood flow response following ischemia of 15 min (reactive hyperemia) fell below baseline values after 4 wk, following an initial increase after 2 wk of exposure. From these results we conclude that the increased blood pressure following prolonged exposure to CIH in healthy humans is associated with sympathetic activation and augmented FVR.

[Management of central sleep apnea]. / Conduite à tenir devant un syndrome d'apnées du sommeil central.

Central sleep apnea is highly prevalent in association with heart failure, some neurological diseases and chronic opioids use. There are two main categories of central sleep apnea respectively related with different underlying conditions. Some hypocapnic patients exhibit respiratory control system instability and central apnea occurs when PaCO(2) falls below the threshold for apnea during sleep. The other group are patients with chronic hypercapnia mainly in the context of neuromuscular disorders or obesity hypoventilation syndrome. All these patients should be assessed by recording blood gases, polysomnography and ventilatory responses to CO(2). Cardiologic assessment should include pro-brain natriuretic factor (pro-BNP) and cardiac echography whereas neurological examination requires brain imaging and/or electromyography. Ventilatory supports used for treating central sleep apnea are non-invasive ventilation and servo-assisted ventilation in hypercapnic and hypocapnic patients respectively.