Restless legs syndrome: Impact on sleep‐related breathing disorders

Restless legs syndrome (RLS) is a common chronic sensory‐motor neurological disorder that remains a clinical diagnosis. Most RLS patients present with sleep complaints in the form of initiation and/or maintenance insomnia as RLS has a circadian rhythmicity. An increased number of periodic leg movements during sleep (PLMS) is a supportive criterion in the diagnosis of RLS. Abnormalities in the central dopaminergic and iron systems are involved in the physiopathology of RLS. There is a higher prevalence of RLS and PLMS in sleep‐disordered breathing patients, particularly those with obstructive sleep apnoea (OSA), the most common sleep disorder in western societies. The complex mechanisms underlying the association between OSA, RLS and PLMS remain unclear. Untreated OSA can lead to adverse cardiovascular consequences due to cardio‐metabolic dysfunction. It remains controversial whether RLS could further adversely impact the cardiovascular consequences of OSA. The PLMS do not have an additive effect on the hypersomnia experienced by some sleep‐disordered breathing patients. Continuous positive airway pressure (CPAP) therapy is the most effective therapy for OSA. The presence of PLMS during CPAP treatment could be a marker of an incomplete resolution of sleep‐disordered breathing in the form of increased upper airway resistance syndrome, despite treatment. Dopaminergic agonists are the preferred agent for the treatment of RLS, and are indicated when RLS symptoms are frequent and affect quality of life. PLMS and RLS do not seem to contribute to the residual hypersomnia that can be observed in some sleep‐disordered breathing patients despite adequate compliance and effective CPAP therapy.     

Treatment of Cheyne-Stokes respiration-central sleep apnea in patients with heart failure

Sleep disordered breathing including obstructive sleep apnea (OSA) and central sleep apnea (CSA) with Cheyne-Stokes respiration (CSR) is often accompanied by heart failure. Treatment of OSA centered on continuous positive airway pressure (CPAP) is established. However, treatment of CSR-CSA is still controversial. Since CSR-CSA occurs as a consequence of heart failure, optimization of heart failure is essential to treat CSR-CSA. For treatment directed at CSR-CSA itself, a variety of treatment approaches including night oxygen therapy and noninvasive positive pressure ventilation have been applied. Among them, night oxygen therapy improves patients' symptoms, quality of life (QOL), and left ventricular function, but had yet been shown to improve clinical outcome. For CPAP, there are responders and non-responders and for responders CPAP can also improve survival. Adaptive servo-ventilation (ASV), which most effectively treats CSR-CSA, improves exercise capacity, QOL, and cardiac function. Recent reports suggested ASV may also prevent cardiac events in patients with heart failure. However, further studies are needed to conclude that this treatment improves patient survival.     

Effectiveness of adaptive servo-ventilation

Adaptive servo-ventilation (ASV) has been developed as a specific treatment for sleep-disordered breathing, in particular Cheyne-Stokes respiration with central sleep apnea (CSA). Heart failure patients often have sleep-disordered breathing, which consists of either obstructive sleep apnea (OSA) or CSA. Other medical conditions, such as stroke, acromegaly, renal failure, and opioid use may be associated with CSA. Continuous positive airway pressure (CPAP) therapy is widely used for patients with OSA, but some of these patients develop CSA on CPAP, which is called treatment-emergent CSA. CPAP can be useful as a treatment for these various forms of CSA, but it is insufficient to eliminate respiratory events in approximately half of patients with CSA. As compared to CPAP, ASV may be a better option to treat CSA, with sufficient alleviation of respiratory events as well as improvement of cardiac function in heart failure patients. In patients without heart failure, ASV can also alleviate CSA and relieve their symptom. Recently, ASV has been widely used for patients with various forms of CSA. ASV may be also used in the setting without CSA, but it should be assessed more carefully. Clinicians should have a better understanding of the indications for ASV in each setting.     

Sleep apnoea in heart failure: To treat or not to treat?

Heart failure (HF) and sleep apnoea are common disorders which frequently coexist. Two main types of apnoea occur: one is obstructive which, through recurring episodes of snoring, hypoxaemia, large negative intra‐thoracic pressures and arousals from sleep leading to downstream inflammatory and autonomic nervous system changes, is thought to be a causative factor to the development of systemic hypertension and HF. The other type of apnoea, Cheyne–Stokes respiration with central sleep apnoea (CSR‐CSA), is characterized by an oscillatory pattern of ventilation with a prevailing hyperventilation‐induced hypocapnia, often in the absence of significant hypoxaemia and snoring, and is thought to be a consequence of advanced HF‐related low cardiac output, high sympathetic nervous system activation and pulmonary congestion. CSR‐CSA may be a compensatory response to advanced HF. Rostral fluid shift during sleep may play an important role in the pathogenesis of both obstructive sleep apnoea (OSA) and CSA. Studies of positive airway pressure (PAP) treatment of OSA and CSA in HF have shown short‐term improvements in cardiac and autonomic function; however, there is no evidence of improved survival. Loop gain may provide useful marker of continuous PAP (CPAP) responsiveness in patients with central apnoea. A greater understanding of the pathophysiology of the interaction between obstructive and central apnoea and the various types of HF, and the mechanisms of therapies, such as PAP, is required to develop new strategies to overcome the disabling symptoms, and perhaps improve the mortality, that accompany HF with sleep apnoea.     

Prevalence and treatment of central sleep apnoea emerging after initiation of continuous positive airway pressure in patients with obstructive sleep apnoea without evidence of heart failure

Background  

This study aimed to assess the prevalence of complex sleep apnoea (CompSA), defined as central sleep apnoea (CSA) emerging after the initiation of continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA), in patients with normal brain natriuretic peptide (BNP) levels, along with assessing the prevalence of CSA persisting in such patients after the onset of CPAP therapy. We hypothesised that the prevalence of CompSA and persistent CSA after CPAP initiation would be low in patients with OSA and normal BNP levels.     

Non‐invasive ventilation for obese patients with chronic respiratory failure: Are two pressures always better than one?

Obesity‐related respiratory failure is increasingly common but remains under‐diagnosed and under‐treated. There are several clinical phenotypes reported, including severe obstructive sleep apnoea (OSA), isolated nocturnal hypoventilation with or without severe OSA and OSA complicating chronic obstructive pulmonary disease (COPD). The presence of hypercapnic respiratory failure is associated with poor clinical outcomes in each of these groups. While weight loss is a core aim of management, this is often unachievable, and treatment of sleep‐disordered breathing with positive airway pressure (PAP) therapy is the mainstay of clinical practice. Although there are few long‐term clinical efficacy trials, the lack of equipoise would prevent the utilization of an untreated control group. The current data support the use of PAP therapy to improve respiratory failure and is associated with improvements in health‐related quality of life, reduced healthcare utilization and reduced mortality. Both continuous PAP (CPAP) and non‐invasive ventilation (NIV) appear safe and effective in patients with obesity‐related respiratory failure and OSA, with or without COPD, and the current evidence would not support a single therapy choice in all patients. There are no studies of CPAP in patients with isolated nocturnal hypoventilation, and NIV would be the current recommendation in this patient group. Whichever starting therapy is used, titration should be performed to correct sleep‐disordered breathing and reverse chronic respiratory failure, with consideration of step‐down of the treatment based on a clinical re‐evaluation. In contrast, failure to reach physiological and clinical treatment targets should lead to the consideration of treatment escalation.     

Pathogenesis of central and complex sleep apnoea

Central sleep apnoea (CSA) – the temporary absence or diminution of ventilatory effort during sleep – is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne–Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, that is elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via continuous positive airway pressure (CPAP), tracheostomy or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep–wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, that is low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, for example CPAP improves lung volume (plant gain), stimulants reduce the alveolar‐inspired PCO₂ difference and supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalized interventions for CSA.     

A novel approach to the treatment of central sleep apnea in patients with heart failure

Central sleep apnea (CSA) is a common, though often unrecognized, finding in congestive heart failure (HF) patients that is associated with poor quality of life and increased morbidity and mortality. While various treatment strategies, including continuous positive airway pressure (CPAP) therapy, have been devised and tested to treat CSA in HF, none thus far have been proven effective over the long term or been shown to improve survival. Adaptive pressure support servo-ventilation (ASV) is a promising potential new therapy for CSA, but like its predecessor, CPAP, it is often not well tolerated by patients, and results from clinical trials evaluating its long-term effectiveness in reducing morbidity and mortality are still a number of years off. Recently, a new therapy utilizing unilateral transvenous phrenic nerve stimulation has been introduced to treat CSA in HF. As a totally implantable, device-based therapy, it may be better tolerated than CPAP or ASV in HF patients and, thus, improve patient compliance with treatment. Early studies using this therapy have been encouraging, with patients demonstrating significant improvement in major indices of CSA severity.     

Dysfunctional breathing treated with continuous positive airway pressure in newly diagnosed obstructive sleep apnoea: a prospective cohort study

A prospective cohort study investigating patients with obstructive sleep apnoea (OSA) was conducted to determine the prevalence of dysfunctional breathing and if continuous positive airway pressure (CPAP) therapy improves associated symptoms. Almost half of newly diagnosed patients with OSA had dysfunctional breathing and CPAP was not an effective treatment. Dysfunctional breathing is common in patients with OSA.     

Sleep apnea and heart failure

Sleep apnea is frequently observed in patients with heart failure (HF). In general, sleep apnea consists of two types: obstructive and central sleep apnea (OSA and CSA, respectively). OSA results from upper airway collapse, whereas CSA arises from reductions in central respiratory drive. In patients with OSA, blood pressure is frequently elevated as a result of sympathetic nervous system overactivation. The generation of exaggerated negative intrathoracic pressure during obstructive apneas further increases left ventricular (LV) afterload, reduces cardiac output, and may promote the progression of HF. Intermittent hypoxia and post-apneic reoxygenation cause vascular endothelial damage and possibly atherosclerosis and consequently coronary artery disease and ischemic cardiomyopathy. CSA is also characterized by apnea, hypoxia, and increased sympathetic nervous activity and, when present in HF, is associated with increased risk of death. In patients with HF, abolition of coexisting OSA by continuous positive airway pressure (CPAP) improves LV function and may contribute to the improvement of long-term outcomes. Although treatment options of CSA vary compared with OSA treatment, CPAP and other types of positive airway ventilation improve LV function and may be a promising adjunctive therapy for HF patients with CSA. Since HF remains one of the major causes of mortality in the industrialized countries, the significance of identifying and managing sleep apnea should be more emphasized to prevent the development or progression of HF.     

Sleep disordered breathing: management update

The term sleep disordered breathing encompasses a spectrum of abnormalities, including snoring, obstructive sleep apnoea (OSA), central sleep apnoea (CSA), respiratory‐related arousals and hypoventilation. This review focuses on both OSA and CSA. It provides a clinical update of recent advances in the diagnosis, management and prognosis of these two conditions. An increasing array of treatment modalities, particularly for OSA, broadens the opportunity for personalised therapy tailored to the individual patient.     

Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes

BACKGROUND: Complex sleep apnea syndrome (CompSAS) is recognized by the concurrence of mixed or obstructive events with central apneas, the latter predominating on exposure to continuous positive airway pressure (CPAP). Treatment of CompSAS or central sleep apnea (CSA) syndrome with adaptive servoventilation (ASV) is now an option, but no large series exist describing the application and effectiveness of ASV. METHODS: Retrospective chart review of the first 100 patients who underwent polysomnography using ASV at Mayo Clinic Sleep Center. RESULTS: ASV titration was performed for CompSAS (63%), CSA (22%), or CSA/Cheyne Stokes breathing patterns (15%). The median diagnostic sleep apnea hypopnea index (AHI) was 48 events per hour (range, 24 to 62). With CPAP, obstructive apneas decreased, but the appearance of central apneas maintained the AHI at 31 events per hour (range, 17 to 47) [p = 0.02]. With bilevel positive airway pressure (BPAP) in spontaneous mode, AHI trended toward worsening vs baseline, with a median of 75 events per hour (range, 46 to 111) [p = 0.055]. BPAP with a backup rate improved the AHI to 15 events per hour (range, 11 to 31) [p = 0.002]. Use of ASV dramatically improved the AHI to a mean of 5 events per hour (range, 1 to 11) vs baseline and vs CPAP (p < 0.0001). ASV also resulted in an increase in rapid eye movement sleep vs baseline and CPAP (18% vs 12% and 10%, respectively; p < 0.0001). Overall, 64 patients responded to the ASV treatment with a mean AHI < 10 events per hour. Of the 44 successful survey follow-up patients contacted, 32 patients reported some improvement in sleep quality. CONCLUSION: The ASV device appears to be an effective treatment of both CompSAS and CSA syndromes that are resistant to CPAP.     

Sleep-disordered breathing in acute decompensated heart failure

Sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and central sleep apnea (CSA), is highly prevalent and frequently unrecognized in patients with chronic heart failure (HF). Untreated SDB may worsen acute decompensation of HF and delay recovery by increasing vascular inflammation and oxidative stress, impeding control of the blood pressure, and promoting arrhythmias. Untreated OSA doubles the risk for developing HF, and patients with HF who develop OSA are thought to have a worse prognosis than patients with HF alone. Similar to the findings in the general population, treatment of OSA appears to reduce cardiovascular morbidity and mortality in HF. The presence of CSA is associated with increased mortality in HF patients. Efficacious suppression of central sleep apnea with continuous positive airway pressure therapy may reduce mortality in HF.     

Sleep Disordered Breathing in Patients with Heart Failure: Pathophysiology and Management

Sleep disordered breathing (SDB) is common in heart failure patients across the range of ejection fractions and is associated with adverse prognosis. Although effective pharmacologic and device-based treatment of heart failure may reduce the frequency or severity of SDB, heart failure treatment alone may not be adequate to restore normal breathing during sleep. Continuous positive airway pressure (CPAP) is the major treatment for SDB in heart failure, especially if obstructive rather than central sleep apnea (CSA) predominates. Adequate suppression of CSA by PAP is associated with a heart transplant-free survival benefit, although randomized trials are ongoing. Bilevel PAP (BPAP) may be as effective as CPAP in treating SDB and may be preferable over CPAP in patients who experience expiratory pressure discomfort. Adaptive (or auto) servo-ventilation (ASV), which adjusts the PAP depending on the patient’s airflow or tidal volume, may be useful in congestive heart failure patients if CPAP is ineffective. Other therapies that have been proposed for SDB in congestive heart failure include nocturnal oxygen, CO₂ administration (by adding dead space), theophylline, and acetazolamide; most of which have not been systematically studied in outcome-based prospective randomized trials.     

Influence of obstructive sleep apnea and treatment with continuous positive airway pressure on fractional flow reserve measurements for coronary lesion assessment

Obstructive sleep apnea (OSA) and sleep‐disordered breathing have been implicated in the progression of cardiovascular disease and with increased risk of coronary artery disease, congestive heart failure, and stroke. Fractional flow reserve (FFR) is used to evaluate the physiological significance of coronary artery stenosis, and this technique is largely thought to be independent of systemic hemodynamic changes. Herein, we describe a case of OSA and sleep‐disordered breathing cyclically altering FFR measurements from normal to abnormal in a patient with coronary artery disease. More specifically, we show that the abnormal FFR across a coronary lesion in a patient with sleep disordered apnea improves (to a normal threshold) with the initiation of continuous positive airway pressure (CPAP). This finding may have implications for the mechanisms of cardiac dysfunction in patients with OSA. © 2009 Wiley‐Liss, Inc.     

The significance and outcome of continuous positive airway pressure-related central sleep apnea during split-night sleep studies

OBJECTIVE: To determine whether central sleep apnea (CSA) occurring during continuous positive airway pressure (CPAP) titration in patients with obstructive sleep apnea (OSA) reflects subclinical congestive heart failure (CHF), and whether these events will improve with CPAP therapy. DESIGN: Cross-sectional analysis of patients with suspected sleep-related breathing disorders referred for split-night polysomnography PATIENTS AND METHODS: Forty-two OSA patients with and without CPAP-related CSA were analyzed. All CSA patients (n = 21) and control subjects (n = 21) underwent echocardiography, pulmonary function testing, and arterial blood gas (ABG) analysis. Repeat polysomnography with CPAP was performed 2 to 3 months after adequate CPAP therapy in CSA group patients. RESULTS: Demographic, Epworth sleepiness scale, pulmonary function test, ABG, and baseline diagnostic polysomnography findings were similar in both groups. There was no difference in the prevalence of subclinical left ventricular systolic dysfunction in the CSA group vs the control group. CSA patients had decreased sleep efficiency (SE), increased sleep stage 1 percentage, sleep stages shift, wake time after sleep onset (WASO), and total arousals compared to control subjects. Twelve of 14 patients (92%) in the CSA group demonstrated complete or near-complete resolution of CSA events on follow-up polysomnography and showed improvement in SE, WASO, and total arousals compared to their baseline study. CONCLUSIONS: CSA events occurring during CPAP titration are transient and self-limited. They may be precipitated by the sleep fragmentation associated with initial CPAP titration and are not associated with an increased prevalence of occult CHF compared to OSA patients without CPAP-related CSA.     

Continuous positive airway pressure in heart failure patients with obstructive sleep apnoea

Background: The aim of the study was to study the effect of 6 months of continuous positive airway pressure (CPAP) in community heart failure (HF) patients with obstructive sleep apnoea (OSA). Methods: Clinically stable outpatients with HF and OSA (left ventricular ejection fraction (LVEF) <45%, apnoea/hypopnoea index >15/h, n = 19) treated with CPAP and a control group (LVEF <45%, apnoea/hypopnoea index <10/h, n = 7) were compared at baseline and at 6 months by Minnesota heart failure score, Epworth sleepiness score, shuttle walk distance, brain natriuretic peptide, urinary catecholamines and echocardiographic indices using paired t‐test, McNemar’s tests and effect sizes. Results: In HF patients with OSA, CPAP improved LVEF (35.9 ± 6.1% to 40.6 ± 8.0%, P = 0.015), decreased LV end‐systolic volume (152 ± 74 to 135 ± 62 cm³, P = 0.03), systolic blood pressure (P = 0.04) and sleepiness (Epworth sleepiness score 8.8 ± 4.8 to 6.3 ± 3.2, P = 0.01), whereas walk distance, catecholamines, brain natriuretic peptide levels and symptoms were unchanged. These outcomes did not change in the HF control group. Conclusion: In community HF patients with OSA, CPAP therapy over 6 months improved LVEF, systolic blood pressure and sleepiness, but not sympathetic activation, brain natriuretic peptide or exercise levels. Acceptance was relatively low, potentially limiting therapeutic effectiveness.     

Long-term treatment with continuous positive airway pressure improves quality of life in obstructive sleep apnoea syndrome.

Continuous positive airway pressure (CPAP) is an established treatment of obstructive sleep apnoea syndrome (OSAS). While it is known that CPAP reverses the pathological breathing pattern and improves daytime sleepiness, there are no sufficient data on the long-term influence of CPAP on quality of life in patients with OSAS. Thirty-nine patients with polysomnographically verified OSAS (apnoea/hypopnoea index (AHI): (mean+/-SD) 46.8+/-21.8 events x h(-1)) were prospectively studied. All patients answered three quality of life measures (Complaint List, Nottingham Health Profile Part 1 (NHP), and Verbal Analogue-Scale "quality of life") prior to the initiation of CPAP therapy. After a mean of 9 months they were re-evaluated by polysomnography, and completed the questionnaires once again. As expected, CPAP was effective in treating the sleep-related breathing disorder. AHI decreased significantly from (mean+/-SD) 46.8+/-21.8 events x h(-1) to 3.3+/-6.3 events x h(-1), and minimum oxygen saturation increased from 77.1+/-9.3% to 89.9+/-3.4%, while body mass index did not change significantly (31.3+/-5.4 versus 30.8+/-4.8 kg x m(-2)). During long-term treatment with CPAP the Complaint List revealed a significant improvement of the extent of subjective impairment due to physical and general complaints (26.4+/-9.9 versus 20.4+/-11.1), and NHP a significant improvement of emotional reactions (19.8+/-21.7 versus 11.1+/-14.0) and energy (50.8+/-36.6 versus 32.1+/-36.7), but not of pain, physical mobility, sleep, social isolation, and quality of life as assessed by the It is concluded that long-term continuous positive airway pressure therapy is effective in improving not only pathological breathing patterns but also parameters that estimate quality of life in patients with obstructive sleep apnoea syndrome.     

Reversal of central sleep apnea using nasal CPAP

Based on the theory that obstructive (OSA) and central (CSA) sleep apneas share common pathophysiologic mechanisms, we attempted to treat eight patients with predominantly CSA by continuous positive airway pressure (CPAP). All patients exhibited repetitive episodes of CSA and mixed sleep apneas (MSA) in the supine position with a mean duration of 23.7 +/- 0.7 s and 34.5 +/- 1.3 s, respectively. The pattern of apnea changed when the subject lay in the lateral position. Five patients were observed to develop OSA in the lateral position with a mean duration of 27.2 +/- 1.5 s, while the other three patients snored continuously. High levels of CPAP (range 9.0 to 16.5 cm H2O) prevented all CSA and MSA and resulted in quiet breathing in all eight patients. Intermediate levels of CPAP produced firstly MSA, then purely OSA and/or continuous snoring. Low levels of nasal CPAP also prevented OSA and snoring occurring in the lateral posture in all subjects (range 2.0 to 8.3 cm H2O). Three patients are currently on home CPAP therapy for a range of four to 36 months. We conclude that upper airway collapse in the supine posture has a key role in the induction of CSA. We suggest that a reflex inhibition of respiration through activation of supraglottic mucosal receptors during passive oropharyngeal airway closure caused CSA in these patients.     

OSA and cardiometabolic risk: What's the bottom line?

Obstructive sleep apnoea (OSA) is a common condition characterized by repetitive upper airway obstruction during sleep. OSA promotes wide intrathoracic pressure swings, intermittent hypoxia and sleep fragmentation. Growing evidence derived from animal models mimicking the oxygen profile observed in patients with OSA as well as clinical studies support that this important sleep‐disordered breathing is associated with increased cardiovascular risk. Although the precise mechanisms are not fully established, it is conceivable that the metabolic deregulation promoted by the components of OSA may have an important causal role in the poor cardiovascular prognosis. In this review, we summarize the potential role of OSA and its components on cardiometabolic disease. We also summarize evidence evaluating the impact of OSA treatment (notably continuous positive airway pressure) on reversing the metabolic deregulation promoted by OSA. Finally, we discuss the research agenda and perspectives for this important research area.