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Objective To test the hypothesis that sleep-related breathing disorder (SRBD) is associated with increasing severity of cardiovascular risk markers. Design A cross-sectional study of sleep laboratory patients. Setting University Hospital Sleep Disorders Centre. Patients We studied 591 patients referred for a sleep study, all of them without a history of systemic hypertension. Interventions Clinical interview, two unattended sleep studies, and assessment of office blood pressure, cholesterol concentration, alcohol and nicotine consumption and daytime blood gases. Main outcome measure Post-hoc analysis of different cardiovascular risk markers: mean blood pressure, pulse pressure, and the type and grade of systemic hypertension. Results Patients were classified as normotensive (blood pressure < 140/90 mmHg, n = 228) or hypertensive (blood pressure ≥ 140/90 mmHg, n = 363) according to office blood pressure measurements. Mixed (systolic and diastolic) hypertension was the most common type of hypertension (n = 182), followed by isolated diastolic hypertension (n = 101), borderline isolated systolic hypertension (n = 70), and isolated systolic hypertension (n = 10). The frequency of mixed hypertension increased with SRBD activity (P< 0.05) and respiratory disturbance index (RDI; the number of breathing disorders per hour of estimated sleep time) was increased in those with mixed hypertension compared with those with normotension (24.8 compared with 15.7; t test: P< 0.01). In hypertensive patients classified as having grades 1 -3 of hypertension (n = 265, 80 and 18, respectively), there was a progressive increase in RDI (18.9, 27.2 and 30.3, respectively, P < 0.01). Mean blood pressure increased significantly with RDI. Pulse pressure increased significantly with age (P < 0.001), but was unrelated to the degree of SRBD. Conclusion We conclude that mean blood pressure and the severity of hypertension, but not pulse pressure, increase with the severity of the SRBD.

Correct assessment of the overall treatment effectiveness requires knowledge about therapy compliance and efficacy. This study aimed to determine overall long-term apnoea alleviation after continuous positive airway pressure (CPAP) in a complete sleep laboratory cohort. Out of 209 consecutive CPAP candidates (mean age 57+/-12 yrs, body mass index (BMI) 30.0+/-5.1 kg x m2, respiratory disturbance index (RDI) 32.9+/-29 h), follow-up treatment was performed in 149 of them at 9, 18 and 30 months after CPAP prescription. Compliance with CPAP (machine run time/days CPAP available) was adjusted for the individual subjective sleep-time. Apnoea alleviation was defined as adjusted compliance multiplied by the CPAP effect (RDI with CPAP applied), remaining RDI was calculated. The baseline RDI, age or BMI in 75 patients, who did not tolerate nasal continuous positive airway pressure (nCPAP), did not differ from those accepting CPAP (acceptors, n=74). In acceptors at 9 months follow-up RDI with CPAP applied was 1.4+/-2.6 (CPAP effect, n=66), mean CPAP use was 3.6+/-2.5 x 24 h(-1) (n=68), mean apnoea alleviation was 52.4+/-32.0% (range 1-100%, n=47), the average remaining whole-night RDI was 17.8+/-26. At 9, 18 and 30 months (n=47), the mean daily CPAP use increased from 3.6+/-2.5 h to 4.1+/-2.5 h and 4.4+/-2.4 h (p

Introduction Electrocardiogram (ECG) based cardiopulmonary coupling (CPC) analysis has been used for assessment of fragmented sleep and sleep disordered breathing. We investigated the relationships between â1- and â2- adrenergic receptor (AR) gene polymorphisms and CPC in a gender-balanced community-dwelling cohort of hypertensive patients and normotensive controls (Skara Sleep Cohort). Materials and methods 280 subjects (137 males, 126 hypertensive patients, age 61.3 ± 6.5 years, BMI 28.5 ± 4.7 kg/m 2 , AHI 24.6 ± 22.1 events/hour) underwent home polysomnography recording. The ECG signal was used to calculate the coupling between heart-rate variability oscillations and ECG-derived respiration. The percentage time spent with high-frequency coupling (HFC, 0.1–0.4 Hz), low-frequency coupling (LFC, 0.01–0.1 Hz) and very low-frequency coupling (VLFC, 0.0039–0.01 Hz) during the sleep period was quantified in subjects with various AR genotypes (â1-[Ser49Gly, Gly389Arg] and â2-[Gly16Arg, Gln27Glu]). Results The â2-AR Arg16 homozygous group had a higher HFC and lower LFC than the Gly16 group independent of gender, total apnea/hypopnea count and sleep efficiency ( p = 0.026 and 0.011, respectively). The â1-AR Arg389 and Gly389 homozygous groups differed in terms of time spent with HFC and VLFC ( p = 0.067 and 0.003, respectively). There was a significant interaction between â2-AR Arg16Gly and â1-AR Arg389Gly polymorphisms such that â2-AR Arg16 homozygotes had further increased HFC and reduced LFC when â1-AR Gly389 allele was present. The â1-AR Ser49Gly and â2-AR Gln27Glu genotypes did not associate with CPC indices. Conclusion The â2-AR Arg16Gly polymorphism influences CPC during sleep. Difference in the â-AR genotype may explain variations in cardiac autonomic modulation during sleep. Acknowledgements The study was supported by the Swedish Heart and Lung Foundation, the Swedish Society of Medicine and the Goteborg Medical Society.

Introduction Carbonic anhydrase inhibition is associated with reduction of apneic events in sleep disordered breathing. Zonisamide has carbonic anhydrase inhibitory properties, and induces weight loss in obese patients. Our aim was to determine the therapeutic effects of zonisamide in obstructive sleep apnea (OSA). Materials and methods Forty-seven patients with moderate to severe OSA and a body mass index 27–35 kg/m2 were randomized to zonisamide, placebo or continuous positive airway pressure (CPAP) treatment for 4 weeks. In the open extension phase, all participants except those on CPAP received zonisamide for 20 weeks. Polysomnography, biochemistry and symptoms were evaluated. Results The placebo controlled effect of zonisamide at 4 weeks was a reduction of apnea hypopnea index (AHI) 33 ± 39% and oxygen desaturation index 28 ± 31% (p = 0.02 and 0.014, respectively). At 24 weeks the mean reduction of AHI after zonisamide and CPAP (adjusted for compliance) was 14 and 61% (p = 0.001 between groups). CPAP but not zonisamide reduced sleepiness. Body weight was marginally changed at 4 weeks but reduced after zonisamide and increased after CPAP at 24 weeks (−2.7 ± 3.0 vs. 2.3 ± 2.0 kg, p Conclusion Zonisamide reduced OSA independent of body weight potentially by mechanisms related to carbonic anhydrase inhibition. Added weight loss after long term zonisamide treatment may generate a further therapeutic potential for this class of drugs in OSA. Acknowledgements The study was supported by the Swedish Heart and Lung Foundation , the Swedish Society of Medicine and the Goteborg Medical Society .

This study investigated whether a drug therapy-induced reduction in nocturnal blood pressure (BP) was associated with decreased sleep apnea activity. Two polysomnographies from 54 hospitalized male hypertensive, obstructive sleep apnea patients were analyzed in a double-blind, randomized, parallel-group trial of the angiotensin-converting enzyme inhibitor cilazapril (C), 2.5 mg once daily, or placebo (P). Blood pressure was measured by means of an intra-arterial catheter. Compared with P, C lowered mean arterial BP during non-rapid eye movement (NREM) (-8.3 +/- 10.7 mm Hg, P = .05) and REM sleep (-8.6 +/- 10.1 mm Hg, P = .02). Respiratory disturbance index (-8.6 +/- 3.2 events/h of sleep (n/h), P = .01) and apnea index (AI) (-6.6 +/- 3.0 n/h, P = .04) during NREM sleep were lowered by C and, to a lesser extent, by P (-5.9 +/- 3.2 n/h, P = .07 and -5.0 +/- 3.6 n/h, P = .18, respectively). The effect on AI and hypopnea index (HI) during REM sleep was not significant for C (-5.9 +/- 3.4 and 0.1 +/- 2.0, NS, respectively) and P (-2.6 +/- 3.9 and 1.6 +/- 2.0, NS, respectively). There was a significant linear correlation between the change in REM systolic BP and the change in REM AI (r = 0.28, P = .04); the mean BP change correlated negatively with the change in HI (-0.28, P = .04). During NREM sleep there was no significant correlation between changes in BP and the treatment effects on sleep apnea activity. Blood pressure reduction after short-term antihypertensive treatment did not affect sleep disordered breathing during NREM sleep. Reduced BP was associated with a weak reduction of AI and a slight increase of HI during REM sleep. It appears that elevated BP contributes only marginally to sleep apnea severity in hypertensive patients with obstructive sleep apnea.

OBJECTIVE To test the hypothesis that sleep-related breathing disorder (SRBD) is associated with poor blood pressure control in hypertensive patients independent from confounding factors such as age, body mass index, alcohol, smoking and daytime blood gases. DESIGN AND METHODS This cross-sectional study of a sleep laboratory cohort was carried out at the University Hospital Sleep Disorders Centre, Marburg. The study comprised 599 patients referred for a sleep study, all of them with a documented history of systemic hypertension and/or previously initiated antihypertensive therapy. Data were obtained from a clinical interview, two unattended sleep studies and assessment of clinic blood pressure, cholesterol level, alcohol and nicotine consumption and daytime blood gases. The main outcome measure was a post hoc analysis of predictors for poor blood pressure control. RESULTS Respiratory disturbance index (RDI) was significantly higher in patients with uncontrolled hypertension (blood pressure > or = 160 and/or 95 mmHg, n = 463) than in those with controlled hypertension (n = 136) (34.0 +/- 26.8 versus 27.0 +/- 23.5, P < 0.01). The relative proportion of patients with uncontrolled hypertension increased significantly as SRBD activity increased (chi2, P< 0.05). Body mass index was the only independent predictor (P = 0.006) of uncontrolled hypertension in the whole study sample. However, in the subset of patients aged < or = 50 years, RDI (P= 0.006) and age (P = 0.016) were the only independent predictors. The probability of uncontrolled hypertension increased by approximately 2% (B = 0.019, P= 0.006) for each RDI unit. CONCLUSION SRBD should be considered, in addition to traditional confounders, as a risk factor for poor blood pressure control in younger hypertensive patients (< or = 50 years of age).

We compared the effects of atenolol (50 mg), amlodipine (5 mg), enalapril (20 mg), hydrochlorothiazide (25 mg), and losartan (50 mg) given in once-daily oral doses on office and ambulatory blood pressures (BPs) in patients with hypertension and obstructive sleep apnea (OSA). Each of 40 randomized patients was treated in sequence with two of the five agents (balanced incomplete block design). Treatment periods lasted 6 wk and were separated by a 3-wk washout period. Changes in BP from baseline with the study substances were compared through analysis of variance. Office diastolic BP, our primary outcome variable, was most effectively lowered by atenolol, with all four post hoc differences between atenolol and the remaining substances being statistically significant. Reductions in office systolic and daytime ambulatory BP were not significantly different among the five compounds. However, atenolol reduced mean nighttime ambulatory diastolic and systolic BP more effectively than did amlodipine, enalapril, or losartan (but not hydrochlorothiazide). Severity of sleep-disordered breathing and well-being during the day were not significantly influenced by any of the study compounds. Our findings are in accordance with the hypothesis that an overactivity of the sympathetic nervous system is an important mechanism behind the development or maintenance of hypertension in patients with OSA.

The exact influence of sleep-related breathing disorder (SRBD) on blood pressure control remains unknown. We investigated the influence of different degrees of SRBD on daytime blood pressure and its association to documented hypertension by examining 1,190 consecutive patients referred for diagnosis of SRBD. The protocol includes clinical interview, physical examination, office blood pressure measurement, cholesterol, and blood gas analysis. Unattended home monitoring of nocturnal breathing was performed for assessment of SRBD activity (respiratory disturbance index [RDI]). RDI was independently and linearly associated with systolic blood pressure (unstandardized coefficient [B] 5 0.07 6 0.03, p 5 0.03), diastolic blood pressure (B 5 0.07 6 0.02, p 5 0 , 0.001), and heart rate (B 5 0.10 6 0.02, p , 0.001) at rest. The relative risk for hypertension (blood pressure > 160/95 mm Hg) increased with SRBD severity (odds ratio [OR], 4.15 for RDI > 40 versus , 5 [95% CI, 2.7 to 6.5]). This relative risk was also elevated in younger ( 40 versus , 5). These cross-sectional clinical data suggest a relationship between SRBD severity and systolic blood pressure, diastolic blood pressure, and heart rate after control for confounders such as body mass index (BMI), age, alcohol/nicotine consumption, cholesterol level, and daytime P O2 and P CO2 . SRBD is an independent risk factor for systemic hypertension with an increased likelihood in subjects < 50 yr of age. Grote L, Ploch T, Heitmann J, Knaack L, Penzel T, Peter JH. Sleep-related breathing disorder is an independent risk factor for systemic hypertension. AM J RESPIR CRIT CARE MED 1999;160:1875‐1882.

Objective To investigate the effects of modafinil, a central nonamphetamine awakening substance, on blood pressure and heart rate in hypersomnolent patients with obstructive sleep apnea. Design This double-blind, randomized, placebo-controlled crossover trial was performed over 2 days and 3 nights in a single-center study of hospitalized patients from a referred care center. Twenty-six otherwise healthy men (age range, 30 to 60 years) with mild to moderate obstructive sleep apnea were recruited by the outpatient department of the Marburg University Sleep Laboratory. Patients were given 200 mg oral modafinil in the morning and 100 mg at midday. Placebo was given in the same manner in a crossover design. Mean arterial (radial) blood pressure was monitored continuously during nocturnal sleep and during a series of standardized daytime physical and psychologic performance tests. Results The difference in the main end point between the treatment with modafinil and placebo was 1.17 ± 0.83 (mean ± SE) mm Hg (95% confidence interval: −0.56 to 2.91 mm Hg). The maximal differences in blood pressure values occurred under loaded conditions (systolic blood pressure, ergometry: 5.62 ± 1.13 mm Hg; mental stress test: 6.19 ± 1.33 mm Hg). Conclusion Short-term administration of modafinil did not elicit a significant response with regard to the main end point. However, cardiovascular effects during mental and physical load were observed. Long-term studies that include subjects with hypertension are necessary to investigate the clinical relevance of the cardiovascular effects of modafinil. Clinical Pharmacology & Therapeutics (1999) 65, 328–335; doi

WCN 2013 No: 2183 Topic: 2 — Movement Disorders Oxycodone/naloxone prolonged-release has positive quality of life outcomes in patients with severe RLS — Results of a 1-year study R. Kohnen, H. Benes, L. Grote, B. Hogl, J. Winkelmann, R.P. Allen, M. Hopp, B. Bosse, C. Trenkwalder. ReSearch Pharmaceutical Services Inc., Nuremberg, Germany; Somni Bene Institute for Clinical Research and Sleep Medicine, Schwerin, Germany; Sleep Disorders Center, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Neurology, Innsbruck Medical University, Innsbruck, Austria; Neurologische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany; Institut fur Humangenetik, Technische Universitat Munchen, Munich, Germany; Institut fur Humangenetik, Helmholtz Zentrum Munchen, Munich, Germany; Neurology Department, John Hopkins University, Baltimore, MD, USA; Mundipharma Research GmbH & Co. KG, Limburg, Germany; Center of Parkinsonism and Movement Disorders

SUMMARY The responses of the upper airway to progressive normocapnic hypoxia were studied in 6 healthy men and in 6 patients with obstructive sleep apnoea syndrome (OSAS). The upper airway resistance was calculated by the ratio of the laryngeal pressure (measured using a catheter introduced into oesophagus) to the inspiratory flow. Additionally, genioglossal EMG activity (GG-EMG) was measured and analysed. The changes of all variables were analysed individually for each subject. The OSAS patients showed reduced ventilatory response, GG-reactivity and changes in upper airway resistance during progressive hypoxia. It is concluded that impaired reactivity to hypoxic activation (probably due to the process of adaptation of carotid chemoreceptors to nocturnal hypoxia), might reduce the defence abilities of OSAS patients against episodes of obturation in upper airway and obstructive apnoea events.

The effect of nasal continuous positive airway pressure (nCPAP) and nasal bi-level positive airway pressure (nBiPAP) on intrathoracic pressure and haemodynamics during wakefulness was studied in a group of nine patients with severe sleep apnoea. No patient took cardiovascular medication. Patients were studied with a Swan Ganz catheter, an arterial line and an oesophageal balloon. nCPAP and nBiPAP were applied in the following pressure sequence: 5, 10 and 15 cm H2O of CPAP and 10/5 and 15/10 cm H2O of nBiPAP. Measurements were made at the end of a 5-min period at each pressure level. Intrathoracic pressure was noted to increase to a level of approximately 50% of the pressure delivered at the mask. At a CPAP of 10 cm H2O and above, as well as at BiPAP of 10/5 or higher, there was a decrease in cardiac output (CO) and cardiac index (CI). CI fell below the normal value in two of the patients. Transmural pulmonary artery pressure (PPAtm) decreased at a CPAP of 15 cm H2O and at both BiPAP levels. Transmural right atrial pressure (PRAtm) decreased at both BiPAP levels. There were no differences in CO, CI, PPAtm and PRAtm between nCPAP and nBiPAP at equal inspiratory pressures. SaO2 increased during BiPAP 15/10 cm H2O, whereas heart rate and arterial blood pressure did not change significantly. The data presented here are consistent with the literature on positive end-expiratory pressure (PEEP) applied via intratracheal tube and are likely to be due to a reduced venous return. It is concluded that nasally applied positive pressure may have acute negative effects on cardiac function in patients with sleep apnoea.

Untersuchungen zu schlafbezogenen Atmungsstorungen (SBAS) im Hinblick auf Epidemiologie, Pathophysiologie und den Einflus auf Morbiditat und Mortalitat zeigen das Bild einer grosen inhomogenen Patientengruppe, die hinsichtlich Alter, Geschlecht, Begleiterkrankungen und Auspragung der SBAS unterschiedliche klinische Beschwerden und Risikoprofile zeigt).

Das vegetative Nervensystem regelt die Organfunktion des Korpers und kontrolliert sein inneres Milieu. Bei ihm lassen sich funktional afferente und efferente Schenkel der Reflexbogen unterscheiden. Afferente Fasern leiten z. B. die Reizungen der Mechano- und Chemorezeptoren aus Lunge und Gefassystem. Efferente Fasern versorgen die glatte Muskulatur der verschiedenen Organe wie das Gefassystem und die Herzfunktionen. An diesen Regelungen sind die Reflexe der Karotisbarorezeptoren sowie die der peripheren arteriellen Chemorezeptoren beteiligt. Sie gehoren zu den am besten untersuchten autonomen Reflexen.

Several studies have shown that there is a high prevalence of sleep-related breathing disorders (SRBD) [9, 14, 18]. Most of these SRBD are caused by sleep apnea, which is characterized by repetitive intermittent cessations of respiration during sleep, lasting for at least 10s. Epidemiologic and polysomnographic studies in sleep laboratories have demontrated the importance of sleep apnea, as they show that patients may be severely endangered by tachycardiac and bradycardiac arrhythmia, arterial and pulmonary hypertension, and apoplectic strokes, depending on the severity of sleep apnea [4, 6, 8, 13, 15, 19].

To assess the effectiveness of cilazapril in regulating blood pressure (BP) in patients with sleep-related breathing disorders, 23 male patients (mean age, 50 years; mean body mass index, 32.7 kg/m2) with a mean apnea/hypopnea index of 49.7 and arterial hypertension (163/104 mm Hg) participated in a placebo-controlled, randomized, double-blind study. They received either cilazapril, 2.5 mg/day (n = 12) or placebo (n = 11). The effects of treatment were studied under different conditions of sleep and physical and mental load before and after 8 days of treatment. Measurements by night included cardiorespiratory polysomnography, inductive plethysmography, pulse oximetry and nasal air flow, electroencephalography, (EEG), electrooculography and electromyography, (ECG), and blood pressure (BP). Measurements by day (ECG, heart rate, and BP) were performed at rest and under physical and mental load. Systolic, diastolic, and mean BP (5 min at night; 1 s during the day), heart rate, apnea and hypopnea index, EEG data, and test reaction times were compared in both groups. The systolic and diastolic BP of patients receiving cilazapril was lower compared to baseline for all physical and mental loads. Mean BP reductions over all standardized loads was greater with cilazapril than placebo (-10 vs. -4.3 mm Hg, p < 0.05). These results show that BP is influenced similarly by mental and physical loads, and that behavior [i.e., awake state and non-rapid eye movement and rapid eye movement (NREM and REM) sleep determines BP regulation. Cilazapril is effective in reducing BP in all situations, especially during REM sleep hypertension.

A new method is presented to study the relationship between reaction time and blood pressure, heart rate and EEG. The method consists of a simultaneous recording of continuous invasive or non-invasive arterial blood pressure, ECG, EEG, EMG and EOG in a sound-isolated chamber while a monotonous visual reaction time test is running for about 90 minutes. The signals are A/D-converted and analyzed digitally after recording. One second average amplitudes are computed. Systolic, mean and diastolic blood pressure values are calculated, and the EEG is divided into the delta, theta, alpha, sigma and beta frequency bands. The signal amplitudes are averaged in three different reaction time categories, i. e., when the reaction is normal, delayed or missing. Preliminary tests suggest that interesting differences can be observed in the studied variables in different reaction time classes. This method can also be applied to the investigation of autonomic control and to treatment studies.