Bilateral hypoglossal nerve stimulation for treatment of adult obstructive sleep apnoea.

BACKGROUND AND AIM: Hypoglossal nerve stimulation (HNS) decreases obstructive sleep apnoea (OSA) severity via genioglossus muscle activation and decreased upper airway collapsibility. This study assessed the safety and effectiveness at 6 months post-implantation of a novel device delivering bilateral HNS via a small implanted electrode activated by a unit worn externally, to treat OSA: the Genio™ system. METHODS: This prospective, open-label, non-randomised, single-arm treatment study was conducted at eight centres in three countries (Australia, France and the UK). Primary outcomes were incidence of device-related serious adverse events and change in the apnoea-hypopnoea index (AHI). The secondary outcome was the change in the 4% oxygen desaturation index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring and device use. This trial was registered with ClinicalTrials.gov, number NCT03048604. RESULTS: 22 out of 27 implanted participants (63% male, aged 55.9±12.0 years, body mass index (BMI) 27.4±3.0 kg·m-2) completed the protocol. At 6 months BMI was unchanged (p=0.85); AHI decreased from 23.7±12.2 to 12.9±10.1 events·h-1, a mean change of 10.8 events·h-1 (p<0.001); and ODI decreased from 19.1±11.2 to 9.8±6.9 events·h-1, a mean change of 9.3 events·h-1 (p<0.001). Daytime sleepiness (Epworth Sleepiness Scale; p=0.01) and sleep-related quality of life (Functional Outcomes of Sleep Questionnaire-10; p=0.02) both improved significantly. The number of bed partners reporting loud, very intense snoring, or leaving the bedroom due to participant snoring decreased from 96% to 35%. 91% of participants reported device use >5 days per week, and 77% reported use for >5 h per night. No device-related serious adverse events occurred during the 6-month post-implantation period. CONCLUSIONS: Bilateral HNS using the Genio™ system reduces OSA severity and improves quality of life without device-related complications. The results are comparable with previously published HNS systems despite minimal implanted components and a simple stimulation algorithm.

Comparison of continuous positive airway pressure and bosentan effect in mildly hypertensive patients with obstructive sleep apnoea: A randomized controlled pilot study.

BACKGROUND AND OBJECTIVE: Randomized controlled trials (RCT) have shown that continuous positive airway pressure (CPAP) has only limited impact on blood pressure (BP). Alternative strategies for obstructive sleep apnoea (OSA)-associated hypertension are therefore needed. Endothelin-1 has been demonstrated a key player in the deleterious cardiovascular consequences of OSA. In OSA, CPAP treatment has never been compared with endothelin receptor antagonist medications. Thus, we assessed the respective efficacy of CPAP and bosentan in reducing 24-h diastolic BP (DBP) in patients with OSA never treated by either therapy. METHODS: In a crossover pilot study, 16 mildly hypertensive patients (office systolic BP (SBP)/DBP: 142 ± 7/85 ± 8 mm Hg) with severe OSA (55 ± 8 years; body mass index, 29.6 ± 4.2 kg/m(2) ; apnoea-hypopnoea index, 40.8 ± 20.2/h) were randomized to either CPAP (n = 7) or bosentan (125 mg/day, n = 9) first for 4 weeks. After 2-weeks of washout, the second 4-week period consisted of the alternative treatment (in crossover). The primary outcome was the 24-h mean DBP change after treatment. RESULTS: In intention-to-treat analysis, the mean difference in 24-h DBP measurements between treatments was -3.1 (-6.9/0.7) mm Hg (median, 25th/75th percentiles) (P = 0.101) with bosentan having a greater effect. CONCLUSION: In this RCT, in mildly hypertensive patients with OSA, bosentan did not modify 24-h DBP but only reduced office BP suggesting that Endothelin-1 blockade does not play a major role in treatment of OSA-related hypertension.

Response to statin therapy in obstructive sleep apnea syndrome: a multicenter randomized controlled trial.

RATIONALE: Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. METHODS: This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. RESULTS: 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m(2). In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (-0.29; 0.28), P = 0.979. Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: -6.34 mmHg (-12.68; -0.01), P = 0.050) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. CONCLUSION: In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695.

Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure.

Hypoxic brain damage might explain persistent sleepiness in some continuous positive airway pressure-compliant obstructive sleep apnea called residual excessive sleepiness. Although continuous positive airway pressure may not be fully efficient in treating this symptom, wake-promoting drug prescription in residual excessive sleepiness is no longer allowed by the European Medicines Agency. The aim of this study is to describe residual excessive sleepiness phenotypes in a large prospective sample of patients with obstructive sleep apnea. Residual excessive sleepiness was defined by an Epworth Sleepiness Scale score ≥ 11. Eligible patients from the French National Sleep Registry attending follow-up continuous positive airway pressure visits numbered 1047. Patients using continuous positive airway pressure < 3 h (n = 275), with residual apnea-hypopnea index > 15 h⁻¹ (n = 31) or with major depression were excluded (n = 150). Residual excessive sleepiness prevalence in continuous positive airway pressure-treated obstructive sleep apnea was 13% (18% for those with an initial Epworth Sleepiness Scale score > 11), and significantly decreased with continuous positive airway pressure use (9% in ≥ 6 h night⁻¹ continuous positive airway pressure users, P < 0.005). At the time of diagnosis, patients with residual excessive sleepiness had worse subjective appreciation of their disease (general health scale, Epworth Sleepiness Scale and fatigue score), and complained more frequently of continuous positive airway pressure side-effects. Residual excessive sleepiness prevalence was lower in severe obstructive sleep apnea than in moderate obstructive sleep apnea (11% when AHI > 30 h⁻¹ versus 18% when AHI 15-30, P < 0.005). There was no relationship between residual excessive sleepiness and body mass index, cardiovascular co-morbidities or diabetes. Continuous positive airway pressure improved symptoms in the whole population, but to a lower extent in patients with residual excessive sleepiness (fatigue scale: -5.2 versus -2.7 in residual excessive sleepiness- and residual excessive sleepiness+ patients, respectively, P < 0.001). Residual excessive sleepiness prevalence decreased with continuous positive airway pressure compliance. Hypoxic insult is unlikely to explain residual excessive sleepiness as obstructive sleep apnea severity does not seem to be critical. Residual symptoms are not limited to sleepiness, suggesting a true 'continuous positive airway pressure-resistant syndrome', which may justify treatment by wake-promoting drugs.

On treatment but still sleepy: cause and management of residual sleepiness in obstructive sleep apnea.

PURPOSE OF REVIEW: Although continuous positive airway pressure (CPAP) treatment effectively reduces sleepiness in obstructive sleep apnea (OSA) patients, some patients remain sleepy in spite of proper treatment. After exclusion or treatment of known causes of sleepiness, residual sleepiness may be diagnosed. Recent changes in approval for currently available wakefulness stimulants in Europe, development of new stimulants and questions about the reality of residual sleepiness prompted this review. RECENT FINDINGS: Prevalence of residual sleepiness is approximately 10% and clearly decreases with increased nightly use of CPAP. Before treatment, patients with residual sleepiness are younger, suffer from less severe OSA and have worse health perception and mood than patients who respond to CPAP. Residual sleepiness is accompanied by other residual symptoms (e.g. fatigue, poor quality of life), suggesting the existence of a 'CPAP resistant syndrome'. Pathophysiological mechanisms remain unclear. Stimulant medication may be beneficial in some patients and is well tolerated. SUMMARY: In spite of a substantial prevalence, residual sleepiness remains still poorly understood and may be difficult to treat. There remains a need for large prospective studies to better define predictive baseline characteristics and further research on causal mechanisms and pharmacological treatments, including large, long-term clinical trials of wakefulness stimulants, is needed.

Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea.

RATIONALE: Randomized controlled trials (RCTs) have shown that continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) reduces blood pressure (BP). CPAP treatment has never been compared with antihypertensive medications in an RCT. OBJECTIVES: To assess the respective efficacy of CPAP and valsartan in reducing BP in hypertensive patients with OSA never treated for either condition. METHODS: In this 8-week randomized controlled crossover trial, 23 hypertensive patients (office systolic BP/diastolic BP: 155 ± 14/102 ± 11 mm Hg) with OSA (age, 57 ± 8 yr; body mass index, 28 ± 5 kg/m(2); apnea-hypopnea index, 29 ± 18/h) were randomized first to either CPAP or valsartan (160 mg). The second 8-week period consisted of the alternative treatment (crossover) after a 4-week washout period. MEASUREMENTS AND MAIN RESULTS: Office BP and 24-hour BP were measured before and at the end of the two active treatment periods. Twenty-four-hour mean BP was the primary outcome variable. There was an overall significant difference in 24-hour mean BP between treatments: the change in 24-hour mean BP was -2.1 ± 4.9 mm Hg (P < 0.01) with CPAP, and -9.1 ± 7.2 mm Hg with valsartan (P < 0.001), with a difference of -7.0 mm Hg (95% confidence interval, -10.9 to -3.1 mm Hg; P < 0.001). The difference was significant not only during daytime but also during nighttime: the change in nighttime mean BP with CPAP was -1.3 ± 4.6 mm Hg (not significant), and -7.4 ± 8.4 mm Hg with valsartan (P < 0.001), with a difference of -6.1 mm Hg (P < 0.05) (95% confidence interval, -10.8 to -1.4 mm Hg). CONCLUSIONS: In an RCT, although the BP decrease was significant with CPAP treatment, valsartan induced a fourfold higher decrease in mean 24-hour BP than CPAP in untreated hypertensive patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT00409487).

Sleep apnea in the elderly: a specific entity?

Sleep apnea is highly prevalent in subjects after age 60, and affects older men and women similarly. Central apneas are often observed in addition to obstructive and mixed events. Pathogenesis of obstructive and central events during sleep in the elderly can be attributed to an amplification of well-established causes of sleep-disordered breathing (SDB) in younger adults. As in middle-aged adults, sleep-related complaints, cardiovascular diseases, depression and traffic accidents should prompt an evaluation by a sleep specialist. However, secondary enuresis and nocturia, cognitive impairment, ophthalmic conditions and repeated falls may be the main complaint in elderly subjects. Sleep studies in the elderly should systematically include reliable means to detect central apneas and periodic leg movements. Untreated SDB in the elderly appears to have a lesser impact on mortality than in middle-aged adults. However, the typical morbidity associated with the disorder in younger adults is observed in the elderly. Elderly symptomatic SDB patients tolerate CPAP no differently than younger patients and should be effectively treated. In conclusion, whether sleep apnea in the elderly represents a specific entity or the same disease as in younger subjects, with some distinctive features, is still unclear. Further research, in particular focusing on the impact of age on SDB outcomes, is needed.

Severe excessive daytime sleepiness induced by hydroxyurea.

Excessive daytime sleepiness (EDS) has been reported with many drugs, either as an extension of a hypnotic effect (e.g. central nervous system depressants) or as an idiosyncratic response of the patient. Here, we report unexpected and severe subjective and objective EDS induced by hydroxyurea therapy, with a favorable outcome after withdrawal. Clinical history, sleep log, polysomnography, and multiple sleep latency tests confirming the absence of other EDS causes are presented.

Which memory processes are affected in patients with obstructive sleep apnea? An evaluation of 3 types of memory.

STUDY OBJECTIVE: To investigate which memory processes are affected by obstructive sleep apnea (OSA). DESIGN: Three separate memory systems were investigated in patients with OSA and normal subjects. Verbal episodic memory was tested after forced encoding, in order to control the level of attention during item presentation; procedural memory was tested using a simplified version of a standard test with an interfering task; lastly, working memory was examined with validated paradigms based on a theoretical model. SETTING: Sleep laboratory and outpatient sleep clinic in a French tertiary-care university hospital. PARTICIPANTS: Ninety-five patients with OSA and 95 control subjects matched for age and level of education. Group 1 (54 patients, 54 controls) underwent an extensive battery of tasks evaluating verbal episodic, procedural, and working memory. Group 2 (16 patients, 16 controls) underwent procedural memory tests only, and group 3 (25 patients, 25 controls) working memory tests only. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Compared with matched controls, patients with OSA exhibited a retrieval deficit of episodic memory but intact maintenance, recognition, and forgetfulness; decreased overall performance in procedural memory, although pattern learning did occur; and impairment of specific working memory capabilities despite normal short-term memory. No consistent correlation was found between OSA severity and memory deficit. The long duration of the test session did not negatively impact the patients' performance. CONCLUSIONS: Memory impairment in OSA is mild and does not affect all memory processes but, rather, specific aspects, underscoring the need for extensive and specific memory testing in clinical and research settings.

Continuous positive airway pressure treatment impact on memory processes in obstructive sleep apnea patients: a randomized sham-controlled trial.

OBJECTIVE: The aim of this study was to investigate the changes in a large panel of memory processes after six weeks of continuous positive airway pressure (CPAP) in obstructive sleep apnea (OSA) patients. This randomized controlled trial compared the influence of effective CPAP to sham CPAP over six weeks on different memory processes in OSA patients. METHODS: The study took place in a sleep laboratory and outpatient sleep clinic in a French tertiary-care university hospital. A total of 36 patients with OSA were randomized to receive either CPAP (n = 18) or sham CPAP (n = 18) for six weeks. Interventions were either effective CPAP or non-effective sham CPAP, for six weeks. All patients underwent an extensive battery of tasks evaluating three separate memory systems, before and after treatment. Verbal episodic memory was tested after forced encoding, procedural memory was tested using simplified versions of mirror drawing and reading tests, and working memory was examined with validated paradigms based on a theoretical model. RESULTS: The study subjects were 55 ± 11 years of age and 72.2% were male. The mean body mass index was 29.5 ± 4.1 kg/m2 and the apnea-hypopnea index was 37.1 ± 16.3/h. Prior to treatment, memory performances of OSA patients were altered. In an intention-to-treat analysis, memory deficits were not significantly improved after six weeks of effective CPAP compared to sham CPAP treatment. Verbal episodic, procedural, and working memory scores were comparable between both groups. CONCLUSION: Using cautious methodology in comparing effective CPAP to sham CPAP and a well-defined set of memory assessments, we did not find improvement in memory performance after six weeks of treatment.

Severe Central Sleep Apnea Associated With Chronic Baclofen Therapy: A Case Series.

Baclofen, a gamma-aminobutyric acid-B agonist with muscle-relaxant properties, is widely used in patients with severe spasticity. In animals, baclofen has been shown to decrease respiratory drive. In humans, however, use of baclofen at the standard dose did not significantly impair sleep-disordered breathing in a susceptible population of snorers. Recently, there has been increasing interest in the role of baclofen for the treatment of alcohol dependence. We describe severe central sleep apnea (CSA) in four patients with none of the conditions commonly associated with CSA who were receiving chronic baclofen therapy for alcohol withdrawal. In one patient, baclofen withdrawal was associated with a complete resolution of CSA. Three patients were treated by adaptive servo-ventilation while continuing their treatment with baclofen. Given the increasing number of patients receiving baclofen for alcohol withdrawal treatment, physicians should be aware that these patients might be affected by severe CSA. Future studies are required to determine the mechanisms, prevalence, and treatment modalities of sleep-disordered breathing associated with baclofen usage.

Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea.

OBJECTIVES: Our aim was to investigate the involvement of the endothelin (ET) system in the cardiovascular consequences of intermittent hypoxia (IH). BACKGROUND: Obstructive sleep apnea (OSA) syndrome is an important risk factor for cardiovascular morbidity. Chronic IH, a major component of OSA, is thought to be responsible for most of the cardiovascular complications occurring during OSA, but the underlying mechanisms remain to be determined. METHODS: Chronic IH was applied in rats genetically prone to develop hypertension (spontaneous hypertensive rats [SHR]) and their normotensive controls. The cardiovascular effects were assessed in vivo and in Langendorff perfused hearts. Hypoxia inducible factor (HIF)-1 activity and targeting of the myocardial ET-1 gene and activation of the ET system were investigated using tissue chromatin immunoprecipitation, enzyme-linked immunoadsorbent assay, immunostaining, and Western blotting. RESULTS: Chronic IH enhanced hypertension development and infarct size in SHR compared with that seen in control rats. This was accompanied by an increase in myocardial big ET-1, ET-1, and ET-A receptor expression and by an enhanced coronary vascular reactivity to ET-1 in SHR only. Myocardial HIF-1 activity was increased, and HIF-1 was shown to be linked to the promoter of the myocardial ET-1 gene after chronic IH only. Moreover, administration of bosentan, a mixed ET receptor antagonist, during chronic IH prevented both the increase in blood pressure and in infarct size. CONCLUSIONS: In SHR, activation of the ET system, mediated by HIF-1 activity, is responsible for the enhanced susceptibility to chronic IH and for its associated cardiovascular consequences leading to hypertension and ischemic injury. Furthermore, the beneficial effects of bosentan suggest exploring ET antagonists as possible therapeutic tools in OSA.