Diagnostic and therapeutic approach of central sleep apnea in heart failure - the role of adaptive servo-ventilation. A statement of the Portuguese society of pulmonology and the Portuguese sleep association.

It is known that patients with heart failure (HF) have an increased risk of developing central sleep apnoea (CSA), with Cheyne-Stokes respiration. The development of servo-ventilation aimed to treat CSA and improve the quality of life (QoL) of these patients. A large randomized clinical study, SERVE-HF, was conducted in order to test this theory in patients with HF and reduced ejection fraction (HFrEF). The results from this trial seemed to indicate that, in these patients, there was no beneficial effect of the assisted ventilation in CSA treatment. More surprisingly, an increased rate of all-cause or cardiovascular mortality was observed. This has led to dramatic changes in clinical practice, with decreased frequency of servo-ventilation prescription across Europe, including Portugal, due to changes in the guidelines. However, SERVE-HF was conducted only in severe systolic HF patients with CSA, and caution must be taken when extrapolating these results to HF patients with preserved ejection fraction or CSA patients without HF. The study also showed poor adherence, methodological and statistical gaps, including study design, patient selection, data collection and analysis, treatment adherence, and group crossovers, which have not been discussed in the trial as potential confounding factors and raise several concerns. Moreover, the adaptive servo-ventilation (ASV) device used in SERVE-HF was unable to lower the minimum support pressure below 3 mm H20, and this has been suggested as one of the probable contributing reasons to the excess mortality observed in this study. This limitation has since been solved, and this ASV device is no longer used. This paper describes the results of a Portuguese Task Force on the treatment of central sleep apnoea in patients with chronic HF.

Hyperlipidaemia prevalence and cholesterol control in obstructive sleep apnoea: Data from the European sleep apnea database (ESADA).

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) and hyperlipidaemia are independent risk factors for cardiovascular disease. This study investigates the association between OSA and prevalence of hyperlipidaemia in patients of the European Sleep Apnea Database (ESADA) cohort. METHODS: The cross-sectional analysis included 11 892 patients (age 51.9 ± 12.5 years, 70% male, body mass index (BMI) 31.3 ± 6.6 kg/m2 , mean oxygen desaturation index (ODI) 23.7 ± 25.5 events/h) investigated for OSA. The independent odds ratio (OR) for hyperlipidaemia in relation to measures of OSA (ODI, apnoea-hypopnoea index, mean and lowest oxygen saturation) was determined by means of general linear model analysis with adjustment for important confounders such as age, BMI, comorbidities and study site. RESULTS: Hyperlipidaemia prevalence increased from 15.1% in subjects without OSA to 26.1% in those with severe OSA, P < 0.001. Corresponding numbers in patients with diabetes were 8.5% and 41.5%, P < 0.001. Compared with ODI quartile I, patients in ODI quartiles II-IV had an adjusted OR (95% CI) of 1.33 (1.15-1.55), 1.37 (1.17-1.61) and 1.33 (1.12-1.58) (P < 0.001), respectively, for hyperlipidaemia. Obesity was defined as a significant risk factor for hyperlipidaemia. Subgroups of OSA patients with cardio-metabolic comorbidities demonstrated higher prevalence of HL. In addition, differences in hyperlipidaemia prevalence were reported in European geographical regions with the highest prevalence in Central Europe. CONCLUSION: Obstructive sleep apnoea, in particular intermittent hypoxia, was independently associated with the prevalence of hyperlipidaemia diagnosis.

Insomnia symptoms combined with nocturnal hypoxia associate with cardiovascular comorbidity in the European sleep apnea cohort (ESADA).

PURPOSE: The aim of the current study was to further investigate the concept of previously reported high occurrence of comorbidities in obstructive sleep patients (OSA) with insomnia-like symptoms. We hypothesized that this finding at least partly is mediated by nocturnal hypoxia. Moreover, we speculated that the spectrum of the clinical OSA phenotypes differs between European geographical regions. METHODS: Cohort of the European Sleep Apnea Database (n = 17,325; 29.9% females) was divided into five subcohorts according to geographical region (North, East, South, West, Central) and further into four clinical presentation phenotypes based on daytime symptoms (EDS) and characteristics suggestive of insomnia. RESULTS: The insomnia phenotype (alone or together with EDS) dominated in all European regions. Isolated insomnia, however, was less common in the West. Insomnia phenotype was associated with the highest proportion of cardiovascular comorbidity (51.7% in the insomnia vs. 43.9% in the EDS type). Measures of nocturnal hypoxemia were independently associated with cardiovascular comorbidity in phenotypes with insomnia-like symptoms. The burden of comorbidities was high across all geographical regions and clinical phenotypes. Regional differences were clinically relevant for age (48 vs. 54 years), BMI (29 vs. 34 kg/m2), and ODI (15 vs. 32/h). CONCLUSION: High prevalence of particularly cardiovascular comorbidity among patients with insomnia-like symptoms was linked to nocturnal hypoxemia. Considerable differences in clinical presentation were found among OSA patients across Europe. Our data underline that physicians should ask their patients with suspected OSA also for insomnia symptoms. It remains to be explored if a reduction of nocturnal hypoxemia predicts the improvement of insomnia symptoms.

Obstructive sleep apnoea syndrome as a cause of road traffic accidents.

UNLABELLED: Several studies have demonstrated that obstructive sleep apnoea syndrome (OSAS) patients have a higher rate of road traffic accidents. Our study aimed to analyse any differences in OSAS patients between those who reported having had road traffic accidents and/or near misses and those who did not. METHODS: We studied 163 patients with OSAS (apnoea- hypopnoea index (AHI)>10/h) diagnosed using nocturnal polysomnography (NPSG), all drivers, 18.4% of whom drove for a living. Patients were asked at their first clinical interview to self-report road traffic accidents and/or near misses over the past 3 years which had been caused by abnormal daytime drowsiness. This allowed patients to be divided into two groups, those who had had road traffic accidents and/or near misses and those who had not. Both were compared as to age, body mass index (BMI), Epworth Sleepiness Scale (ESS), daytime PaO2 and PaCO2, Functional Outcomes of Sleep Questionnaire (FOSQ) test and NPSG data. This latter was total sleep time (TTS), sleep efficiency, sleep stages, arousal index (ARI), AHI, minimal and average SaO2, % of time with SaO2 < 90% (T90), desaturation index (ODI), total duration of apnoea-hypopnoea (TDAH) (T test). RESULTS: Group I (no road traffic accidents) No=89 patients; group II (road traffic accidents) No=74 patients. Age (years) was 57.6+/-11.8 vs. 54.7+/-10.9 (ns); male gender, 75% vs. 78.4%; ESS, 12.3+/-5.4 vs. 17.6+/-4.3 (p<0.001); BMI, (Kg/m2) 36.2+/-8.1 vs. 35.6+/-6.3 (ns); PaO2 (mmHg), 76.1+/-11.4 vs. 78.5+/-12.6 (ns); PaCO2 (mmHg), 42.6+/-5.1 vs. 42.2+/-4.7 (ns); FOSQ, 15.1+/-3.1 vs. 12.9+/-3.4 (p<0.001). NPSG data revealed differences only in AHI: 45.0+/-21.6 vs. 56.2+/-29.7 (p=0.01) and in TDAH (minutes), 98.5+/-63.7 vs. 133.3+/-83.2 (p=0,005). CONCLUSIONS: In our experience patients who had road traffic accidents and/or near misses had a more severe OSAS, with higher AHI, excessive daytime sleepiness and lower quality of life.

Regulation of brain-derived neurotrophic factor (BDNF) during sleep apnoea treatment.

BACKGROUND: Patients with obstructive sleep apnoea syndrome (OSAS) often display persistent cognitive dysfunction despite effective treatment with continuous positive airway pressure (CPAP). Brain-derived neurotrophic factor (BDNF) is a key mediator of memory and cognition, but its regulation in OSAS and during CPAP treatment is unknown. METHODS: Serum and plasma BDNF concentrations, BDNF secretion by peripheral blood mononuclear cells, and overnight polysomnography were evaluated in 17 men with newly diagnosed OSAS (as defined by a respiratory disturbance index of >10/hour with >70% obstructive events and corresponding daytime symptoms) and 12 healthy control men. In the patients all the parameters were monitored after 1 night and 3 months of CPAP treatment. RESULTS: There was no significant difference in baseline serum BDNF, plasma BDNF, or spontaneous BDNF secretion by peripheral blood mononuclear cells between untreated patients and controls. After 1 night of CPAP treatment there was a steep fall in median serum BDNF (from 18.0 ng/ml to 4.1 ng/ml) and plasma BDNF (from 58.7 pg/ml to 22.0 pg/ml) concentrations. Following 3 months of treatment BDNF concentrations did not return to baseline. In contrast, BDNF secretion was not suppressed by CPAP treatment. CONCLUSIONS: Patients with untreated OSAS have normal serum and plasma BDNF levels. CPAP treatment is associated with a rapid decrease in serum and plasma BDNF levels which may reflect enhanced neuronal demand for BDNF in this condition.

[Endoscopically-assisted adjustment of an oral appliance in patients with obstructive sleep apnoea]. / Endoskopisch kontrollierte Adjustierung der Unterkiefervorverlagerung zur Optimierung von intraoralen Protrusionsgeräten in der Therapie des obstruktiven Schlafapnoe-Syndroms.

BACKGROUND: The treatment effect of patients suffering from obstructive sleep apnoea/hypopnea (OSAHS) with an oral appliance is considerably varied, and its clinical outcome is unpredictable. The aim of our investigation was to examine the changes in pharyngeal airway size at different degrees of mandibular protrusion in order to assess the therapeutic efficacy in relation to the amount of protrusion. METHODS: Fifteen patients with the polysomnographic diagnosis of mild to moderate OSAHS were included in this prospective study. Nasal video endoscopy of the pharynx was done with the patients in supine position at four different degrees of mandibular protrusion do assess the changes of airway size. After 3 - 4 weeks a control polysomnography was carried out, with the mandible in optimal protrusion. RESULTS: The pharyngeal diameter did not increase linearly to the amount of mandibular protrusion. In the polysomnographic examination the respiratory variables were significantly increased. None of the patients in this group was classified as a non-responder to the oral appliance therapy. CONCLUSIONS: The endoscopically-assisted adjustment of the mandibular protrusion appliance is an additional tool to optimise treatment effectiveness. The increase in pharyngeal diameter is not proportional to the amount of mandibular protrusion.

[Long term compliance with an oral protrusive appliance in patients with obstructive sleep apnoea]. / Obstruktive Schlafatmungsstörungen: Therapiecompliance mit einem intraoralen Protrusionsgerät.

BACKGROUND AND OBJECTIVE: Oral protrusive devices (OPD) are increasingly used in primary snoring and mild-to-moderate obstructive sleep disordered breathing. Due to evidence of reduced compliance with the well established standard treatment of nasal positive airway pressure (CPAP) and reports of patient preference for OPD treatment, particularly in mild cases, OPD may be considered another treatment alternative. PATIENTS AND METHODS: We contacted 192 patients suffering from obstructive sleep breathing disorder, who were treated between May 1996 and September 2001 with an OPD. The patients" use of the device was evaluated, as were any reasons for ceasing to use the device. RESULTS: 105 patients (54.4%) regularly used the appliance after a mean time of 22.7 12.3 month. 21 patients (10.9%) showed no primary compliance and stopped had using the device before the first somnographic follow-up after a mean time of 3.8 months. In this investigation 76 patients (80,2%) were classified as responders and 19 patients (20.8%) as primary non-responders. 22 responders (11.4%) demonstrated no secondary compliance after a mean of 21.9 8.8 months and the discontinued OPD treatment themselves. In 21 patients (10.9%) the nightly respiratory parameters decreased after a mean of 23.0 11.7 months; hence, those patients required CPAP. The cumulative risk using the device after four years as prescribed was 32.2%. We found a correlation between patient compliance, body-mass index and the amount of teeth in the upper and lower jaws. CONCLUSION: OPD compliance seems to be lower than frequently expected. Regular follow-up investigations are necessary to ensure adequate treatment. Poor dental status and an excess body-mass index reduce patient compliance.

[Intraoral protrusion devices in obstructive sleep apnea. Dental findings and possible treatments]. / Intraorale Protrusionsgeräte bei schlafbezogenen obstruktiven Atmungsstörungen. Zahnärztliche Befunde und Behandlungsmöglichkeiten.

BACKGROUND: Oral protrusive devices are regarded as an alternative treatment option for snoring and mild to moderate obstructive breathing disorders. In addition to the polysomnographic indication based on the respiratory and somnographic findings, healthy stomatognatic conditions with sufficient dental retention for the device are essential for a successful treatment. PATIENTS AND METHODS: The sleep laboratory of the University Hospital of Freiburg i. Br. referred 112 patients with obstructive sleep apnea to the Department of Orthodontics for treatment with an oral protrusive device. All patients were examined clinically and with a panoramic radiograph with regard to continuous treatment. RESULTS: To maximize treatment success and minimize dental side effects, close collaboration with dental colleagues is necessary in treatment with an oral protrusive device. CONCLUSIONS: Acute periodontitis, periodontal lesions, insufficient dental anchorage, and temporomandibular symptoms can result in unwanted dental side effects and therefore limit the indication of this therapeutic approach.

Occlusal side effects caused by a mandibular advancement appliance in patients with obstructive sleep apnea.

Mandibular advancement appliances (MAA) have been established as an alternative treatment option for obstructive sleep apnea (OSA). Although the therapeutic effect of these devices has been proven both clinically and polysomnographically through various studies, there are very few follow-up examinations in existence concerning possible dental side effects caused by the MAA. However, if lifelong treatment of OSA is considered, these follow-up examinations are of utmost importance. This article presents 2 cases with unexpected dental side effects and occlusal alterations caused by MAA therapy.

Change in perforin-positive peripheral blood lymphocyte (PBL) subpopulations following exercise.

Perforin, one of the cytotoxic proteins of the immune system, plays a prominent role in protection against viral and bacterial infections. We investigated its expression in PBL and their CD3+, CD4+, CD8+ and CD16+ and/or CD56+ subpopulations in endurance athletes before and after a triathlon. Lymphocyte subpopulations were analysed by flow cytometry following separation of peripheral blood mononuclear cells and staining with antibodies against specific membrane antigens and intracellular perforin. The number of total lymphocytes decreased from 2.1 x 10(3)/microl before the triathlon to 1.0 x 10(3)/microl 1 h after the triathlon (P < 0.01). Interestingly, there was already a significant spontaneous decline in the percentage of CD3+/perforin+, and in CD8+/perforin+ cells, in the week proceeding the triathlon, when subjects were instructed to refrain from strenuous exercise training. The percentage of CD3+/perforin+, CD8+/perforin+ and CD16+ and/or CD56+/perforin+ cells in each lymphocyte subpopulation decreased 1 h after exercise even further from 14.3% to 5.8% (P < 0.05), 18.5% to 6.5% (P < 0.05) and 77.3% to 67.3%, respectively. However, at 18 h and 48 h after exercise the percentage of perforin-expressing CD3+, CD8+ and CD16+/56+ cells increased again towards baseline levels. Compared with normal controls, baseline perforin co-expression in CD3+ and CD8+ lymphocytes was significantly higher in trained athletes. From our data we conclude that trained athletes have an increased percentage of perforin+ PBL and that following exercise the percentage of perforin+ and therefore potentially cytotoxic lymphocytes transiently decreases in peripheral blood.

Increase in perforin-positive peripheral blood lymphocytes in extrinsic and intrinsic asthma.

The cause of asthma, which has been linked to a chronic, T-cell-mediated bronchial inflammation, remains unclear. A number of other T-lymphocyte-mediated, chronic inflammatory disorders have been associated with autoimmunity and there are data indicating that autoimmune phenomena might also be present in asthma. Expression of perforin, a cytotoxic molecule produced by lymphocytes, has been implicated in the pathogenesis of autoimmune diseases. We therefore tested the hypothesis that allergic and intrinsic asthma might be associated with an increase in lymphocytes producing perforin by comparing the expression of intracellular perforin in peripheral blood lymphocytes of patients with extrinsic asthma (n = 13), intrinsic asthma (n = 7), and healthy control subjects (n = 18). Lymphocytes were identified using flow cytometry and subdivided into CD3(+), CD4(+), CD8(+), CD16(+), and CD56(+) subpopulations after staining with appropriate monoclonal antibodies. The percentage of perforin-positive total lymphocytes was significantly elevated in patients with allergic as well as intrinsic asthma when compared with normal control subjects. Analysis of lymphocyte subpopulations also revealed a significant increase in the percentage of CD3(+), CD4(+), CD8(+), and CD56(+) cells expressing perforin in allergic asthma and a significant increase in the percentage of CD4(+) and CD56(+) cells in intrinsic asthma when compared with healthy control subjects. Perforin expression in CD4(+) cells in intrinsic asthma was also significantly elevated compared with allergic asthma. We conclude that allergic and intrinsic asthma is associated with increased expression of perforin in T-lymphocyte subsets.

[Increase in perforin-positive peripheral blood lymphocytes in extrinsic and intrinsic asthma]. / Perforin-positive Lymphoozytem im peripheren Blut bei extrinsischem undintrinsischem Asthema.

The cause of asthma which has been linked to a chronic, T-cell-mediated bronchial inflammation, remains unclear. A number of other T-lymphocyte-mediated, chronic inflammatory disorders have been associated with autoimmunity and there are data indicating that autoimmune phenomena might also be present in asthma. Expression of perforin, a cytotoxic molecule produced by lymphocytes, has been implicated in the pathogenesis of autoimmune disease. We therefore tested the hypothesis that allergic and intrinsic asthma might be associated with an increase in lymphocytes producing perforin by comparing the expression of intracellular perforin in peripheral blood lymphocytes of patients with extrinsic asthma (n = 13), intrinsic asthma (n = 7), and healthy (control subjects (n = 18). Lymphocytes were identified using flow cytometry and subdivided into CD3(+), CD4(+), CD8(+), CD16(+), and CD56(+) subpopulations after staining with appropriate monoclonal antibodies. The percentage of perforin-positive total lymphocytes as significantly elevated in patients with allergic as well as intrinsic asthma when compared with normal control subjects. Analysis of lymphocyte subpopulations also revealed a significant increase in the percentage of CD3(+), CD4(+), CD8(+), and CD56(+) cells expressing perforin in allergic asthma and a significant increase in the percentage of CD4(+), and CD56(+) cells in intrinsic asthma when compare with healthy control subjects. Perforin expression in CD4(+) cells in intrinsic asthma was also significantly elevated compared with allergic asthma. We conclude that allergic and intrinsic asthma is associated with increased expression of perforin in T-lymphocyte subsets.

Development of image analysis demonstration packages with MENU: educational aspects.

In this paper a tool, MENU, is presented, with which demonstration packages can be easily constructed. The teacher designs the set-up of the package by editing a demonstration specification file, containing both commands to MENU to display frames to the end-user or to execute tasks and the text of the frames. The text contains explanations for the end-user together with the options he can choose. MENU takes care that the corresponding actions are executed. Two image analysis packages, one about CT and one about gated cardiac bloodpool scintigraphy, are presented as examples of the use of MENU. It is concluded, that with MENU (existing) programs can be modeled into packages very easily and efficiently. MENU proves to be a tool that is worthwhile for educational purposes.