Treatment of sleep-disordered breathing with positional therapy: long-term results.

PURPOSE: The aim of the present study was to assess the efficacy of a sleep position trainer (SPT) in patients with an established diagnosis of positional obstructive sleep apnea and to evaluate the adherence after 1-year follow-up. METHODS: Polysomnography (PSG) was performed at baseline and after 1 year of SPT use. Patients received questionnaires to assess treatment satisfaction and subjective adherence. Data on objective adherence and number of vibrations initiated by the SPT were collected from the SPT device. RESULTS: Nine out of 58 patients stopped using the SPT during the first year of treatment (16%). Thirty-four middle-aged and overweight patients underwent a PSG after 1 year of SPT use (male/female ratio, 28/6; overall apnea/hypopnea index (AHI), 16/h). A significant reduction in overall AHI to 6/h was observed using treatment (p < 0.001). The median percentage of supine sleep decreased significantly to 1% with SPT (p < 0.001). The mean objective SPT use in 28 patients was 7.3 ± 0.9 h/night and 69 ± 26% of the nights. Furthermore, 75% of the patients reported a better sleep quality since the start of SPT treatment. CONCLUSIONS: Long-term treatment with the SPT was found to be effective in reducing overall AHI. Time spent sleeping in supine position was reduced to almost zero in the continuing users. Patient satisfaction was high when using the SPT.

Treatment of obstructive sleep apnea using a custom-made titratable duobloc oral appliance: a prospective clinical study.

PURPOSE: This prospective clinical study investigates the efficacy of a specific custom-made titratable mandibular advancement device (MAD) for the treatment of obstructive sleep apnea (OSA). This MAD has attachments in the frontal teeth area that allow for progressive titration of the mandible. METHODS: Sixty-one adult OSA patients were included (age, 46.7 ± 9.0 years; male/female ratio, 45/16; apnea-hypopnea index (AHI), 23.2 ± 15.4 events/h sleep; body mass index, 27.9 ± 4.1 kg/m²). After an adaptation period, titration started based on a protocol of symptomatic benefit or upon reaching the physiological limits of protrusion. As a primary outcome, treatment response was defined as an objective reduction in AHI following MAD treatment of ≥50 % compared to baseline, and treatment success as a reduction in AHI with MAD to less than 5 and 10 events/h sleep. Compliance failure was defined as an inability to continue treatment. RESULTS: A statistically significant decrease was observed in AHI, from 23.4 ± 15.7 at baseline to 8.9 ± 8.6 events/h with MAD (p < 0.01). Treatment response was achieved in 42 out of 61 patients (68.8 %), whereas 42.6 % met criteria of AHI < 5 and 63.9 % achieved an AHI < 10 events/h sleep, respectively. Four patients (6.6 %) were considered as "compliance failures." CONCLUSIONS: The present study has evaluated the efficacy of a specific custom-made titratable MAD in terms of sleep apnea reduction.

Sleep-disordered breathing and the metabolic syndrome in overweight and obese children and adolescents.

OBJECTIVE: To assess whether sleep-disordered breathing (SDB) is a risk factor of the metabolic syndrome (MS) in children and adolescents who are overweight and to examine whether the severity of SDB was independently associated with glucose intolerance, insulin resistance, and/or dyslipidemia. STUDY DESIGN: Consecutive subjects who were overweight or obese underwent polysomnography, fasting blood sample, and oral glucose tolerance test (for calculation of area under the curve [AUC]). SDB was defined as a respiratory disturbance index > or = 2. MS was present when > or = 3 of these factors were present: waist circumference > or = 90th percentile; fasting glucose level > or = 110 mg/dL; triglyceride level > or = 110 mg/dL; high-density lipoprotein cholesterol level < or = 40 mg/dL; blood pressure > or = 90th percentile. RESULTS: A total of 104 subjects were included in the study (44% boys; 58% prepubertal; mean age, 11.1 +/- 2.6 years; 69% obese). Mean SaO2 (odds ratio, 0.54) and SaO2nadir (odds ratio, 0.89) were independent, significant predictors of the presence of MS. Multiple regression showed significant associations between SaO2nadir and high-density lipoprotein cholesterol level, mean SaO2 and both AUC glucose and triglyceride levels, and between the percentage of total sleep time with SaO2 > or = 95% and cholesterol level, while controlling for adiposity and sex, puberty, or both. CONCLUSION: This study supports the hypothesis of an interaction between SDB and metabolic abnormalities, independent of estimates of body fat distribution, in children and adolescents who are overweight and obese.

Reference values for sleep-related respiratory variables in asymptomatic European children and adolescents.

AIM: Only a limited number of studies, designed to establish normal values for sleep-related respiratory variables in children, have been reported, and all are non-European. The aim of this study was to expand the knowledge on normative data in children. METHODS: Subjects ranging from 6 to 16 years were recruited and underwent full polysomnography. Only subjects without sleep disordered breathing or other sleep problems as assessed by clinical history were included. RESULTS: Sixty subjects were studied ( = 11.7 +/- 2.6 years; 28 boys; = 118.8 +/- 30.6%). was 0.85 +/- 1.06 (range: 0.0-5.5). was 0.06 +/- 0.16 (range: 0.0-0.9); 11 patients had a total of 31 obstructive apneas. Only five obstructive hypopneas were detected with = 0.08 +/- 0.17 (range: 0.0-0.9). was 1.98 +/- 1.39 (range: 0.1-7.2). was 97.0 +/- 0.6% (range: 96.0-98.0); was 91.8 +/- 2.7% (range: 82.0-96.0); <% of total sleep time with SaO2 >or= 95%> was 98.7 +/- 2.1% (range: 90.8-100.0); was 0.8 +/- 0.9 (range: 0.0-4.9) and was 6.1 +/- 1.8 (range: 2.7-10.9). Snoring was detected in 15 patients (4 overweight subjects), with no difference in patient characteristics and sleep-related respiratory variables between snorers and non-snorers. Subjects in the overweight group (n = 22) had a lower SaO2nadir (90.8 +/- 2.7 vs. 92.4 +/- 2.6; P = 0.01) and a higher ODI (1.3 +/- 1.3 vs. 0.4 +/- 0.4; P = 0.0002) than their normal weight peers. CONCLUSION: Our data are in agreement with other non-European studies, designed to establish normal values in children.

Is wheezing associated with decreased sleep quality in Sri Lankan children? A questionnaire study.

AIM: To investigate the association between wheezing and impaired sleep in Sri Lankan children, aged 6-12 years; and, to report the prevalence of asthma-related symptoms in these subjects. METHODS: The International Study of Asthma and Allergies in Childhood questionnaire and a separate sleep questionnaire were completed. RESULTS: Of 800 originally distributed questionnaires, 652 were analyzed. Wheezing was present in 89 children (14%). Within this group, 66% reported wheezing in the last 12 months. Wheezing children had a significantly higher presence of snoring, restless sleep, nocturnal awakenings and daytime tiredness. Wheezing was found to be independently associated with restless sleep (odds ratio (OR) = 2.4). There was no association between wheezing and difficulties falling asleep, nocturnal awakenings, apneas, and daytime sleepiness and tiredness. After adjusting for possible confounders, the following significant associations were present: snoring and apneas (OR = 1.6), chronic rhinitis and apneas (OR = 1.6), snoring and restless sleep (OR = 3.2), chronic rhinitis and restless sleep (OR = 2.1), and hayfever and daytime tiredness (OR = 4.3). Wheezing was related to an increased risk of snoring (OR = 2.8) and subjects with chronic rhinitis had also an increased risk of snoring (OR = 1.7), adjusting for possible confounders. CONCLUSION: The sleep of wheezing children was impaired compared with their non-wheezing peers, resulting in an increased prevalence of daytime tiredness. Upper airway symptoms, such as chronic rhinitis or hayfever, should be carefully considered in these children, as they might be responsible for these sleep problems.

Glucocorticosteroids as antioxidants in treatment of asthma and COPD. New application for an old medication?

Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in the treatment of patients with COPD. The influence of steroids on inflammatory processes has long been established since glucocorticoids and their receptor belong to the regulatory network involved in inhibition of several inflammatory pathways. Inflammatory processes are usually accompanied by an increased oxidative burden followed by a depletion of antioxidants. Therefore, the effects of steroids on antioxidant status have been investigated revealing possible positive effects on the reduced antioxidant enzyme activity. Nevertheless, the mechanisms of this modulation have not been fully elucidated yet. It is possible that antioxidant enzyme activity is regulated at the level of transcription. Additionally, because of the fact that antioxidant enzymes are trace element dependent, steroids may affect their activity through influence on trace element accumulation. This review summarizes the effects of steroids on the antioxidant enzymes activity in vitro and in vivo in relation to asthma and COPD.

Functional imaging using computational fluid dynamics to predict treatment success of mandibular advancement devices in sleep-disordered breathing.

Mandibular advancement devices (MADs) have emerged as a popular alternative for the treatment of sleep-disordered breathing. These devices bring the mandibula forward in order to increase upper airway (UA) volume and prevent total UA collapse during sleep. However, the precise mechanism of action appears to be quite complex and is not yet completely understood; this might explain interindividual variation in treatment success. We examined whether an UA model, that combines imaging techniques and computational fluid dynamics (CFD), allows for a prediction of the treatment outcome with MADs. Ten patients that were treated with a custom-made mandibular advancement device (MAD), underwent split-night polysomnography. The morning after the sleep study, a low radiation dose CT scan was scheduled with and without the MAD. The CT examinations allowed for a comparison between the change in UA volume and the anatomical characteristics through the conversion to three-dimensional computer models. Furthermore, the change in UA resistance could be calculated through flow simulations with CFD. Boundary conditions for the model such as mass flow rate and pressure distributions were obtained during the split-night polysomnography. Therefore, the flow modeling was based on a patient specific geometry and patient specific boundary conditions. The results indicated that a decrease in UA resistance and an increase in UA volume correlate with both a clinical and an objective improvement. The results of this pilot study suggest that the outcome of MAD treatment can be predicted using the described UA model.

The interrelationship between markers of inflammation and oxidative stress in chronic obstructive pulmonary disease: modulation by inhaled steroids and antioxidant.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is accompanied by both airway and systemic inflammation and by oxidative stress. This study aimed to characterise the relationship between oxidative stress and inflammatory components in induced sputum and blood. MATERIAL & METHODS: We studied blood and sputum samples from stable COPD patients (mean FEV1 60.5+/-7.5% predicted) at baseline (no treatment) and after 10 weeks treatment with either inhaled steroid, fluticasone propionate (FP) (1000 microg/d) or 10 weeks treatment with N-acetylcysteine (600mg/d) (NAC). We assessed the inflammatory markers (IL-8, ECP, sICAM-1, NE) in sputum and serum and we compared them with blood markers of oxidative stress (SOD, GPx, TEAC, albumin, vitamin E and A). RESULTS: At baseline blood sICAM-1 correlated with IL-8 levels (P<0.01, r = 0.62) and negatively with GPx (P<0.01, r = -0.63) and with TEAC (P<0.05, r = -0.53). TEAC correlated positively with GPx (P<0.01, r = 0.70). Correlation between sICAM and IL-8 disappeared after NAC treatment. The correlation between sICAM and GPx disappeared after FP treatment. The correlation between TEAC and GPx was maintained after both NAC and FP. CONCLUSIONS: The relationship between markers of inflammation, adhesion and antioxidant capacity is significantly modulated by treatment with N-acetylcysteine or inhaled corticosteroids.

Abbreviated method for assessing upper airway function in obstructive sleep apnea.

STUDY OBJECTIVES: Previous studies have shown that the level of flow through the upper airway in patients with obstructive sleep apnea (OSA) is determined by the critical closing pressure (Pcrit) and the upstream resistance (RN). We developed a standardized protocol for delineating quasisteady-state pressure-flow relationships for the upper airway from which these variables could be derived. In addition, we investigated the effect of body position and sleep stage on these variables by determining Pcrit and RN, and their confidence intervals (CIs), for each condition. DESIGN: Pressure-flow relationships were constructed in the supine and lateral recumbent positions (nonrapid eye movement [NREM] sleep, n = 10) and in the supine position (rapid eye movement [REM] sleep, n = 5). SETTING: University Hospital Antwerp, Belgium. PATIENTS: Ten obese patients (body mass index, 32.0+/-5.6 kg/m(2)) with severe OSA (respiratory disturbance index, 63.0+/-14.6 events/h) were studied. INTERVENTIONS: Pressure-flow relationships were constructed from breaths obtained during a series of step decreases in nasal pressure (34.1+/-6.5 runs over 3.6+/-1.2 h) in NREM sleep and during 7.8+/-2.2 runs over 0.8+/-0.6 h in REM sleep. RESULTS: Maximal inspiratory airflow reached a steady state in the third through fifth breaths following a decrease in nasal pressure. Analysis of pressure-flow relationships derived from these breaths showed that Pcrit fell from 1.8 (95% CI, -0.1 to 2.7) cm H(2)O in the supine position to -1.1 cm H(2)O (95% CI, -1.8 to 0.4 cm H(2)O; p = 0.009) in the lateral recumbent position, whereas RN did not change significantly. In contrast, no significant effect of sleep stage was found on either Pcrit or RN. CONCLUSIONS: Our methods for delineating upper airway pressure-flow relationships during sleep allow for multiple determinations of Pcrit within a single night from which small yet significant differences can be discerned between study conditions.

Angiotensin-converting enzyme activity in serum and bronchoalveolar lavage fluid after damage to the alveolo-capillary barrier in the human lung.

OBJECTIVE: Angiotensin-converting enzyme (ACE) is considered as a possible marker for endothelial cell damage in serum or bronchoalveolar lavage fluid. This hypothesis was tested during cardiac surgery and during the adult respiratory distress syndrome. DESIGN: We used patients with an expected different degree of endothelial cell damage. ACE levels in serum and bronchoalveolar lavage fluid were compared with indirect markers of alveolo-capillary barrier integrity. SETTING: Interdisciplinary team in a university hospital. METHODS: 13 Cardiac surgery patients received no glucocorticoids and 13 others received 2 g methylprednisolone before extracorporeal circulation. Thirteen patients were used as controls and 15 patients had nonseptic adult respiratory distress syndrome. All underwent bronchoalveolar lavage for ACE determination. RESULTS: At different times during surgery serum angiotensin-converting enzyme levels were not significantly different between the two groups. In post-operative bronchoalveolar lavage fluid, angiotensin-converting enzyme levels were significantly higher in patients who received corticoids (27.8 +/- 1.7 U/l, mean +/- SEM), compared to patients without corticoids (19.8 +/- 1.4 U/l), control patients (18.2 +/- 1.3 U/l) or patients with full blown non-septic adult respiratory distress syndrome (18.8 +/- 1.1 U/l). There were no correlations between lavage angiotensin-converting enzyme and other parameters for alveolo-capillary membrane integrity in the lavage fluid such as the number of neutrophil cells, albumin or protein concentration, and between lavage angiotensin-converting enzyme and PaO2/FIO2 ratio during lavage. CONCLUSION: Angiotensin-converting enzyme activity in serum or bronchoalveolar lavage fluid does not reflect damage of endothelial cells or damage of alveolocapillary integrity in acute pulmonary disease.

N-acetylcysteine pretreatment of cardiac surgery patients influences plasma neutrophil elastase and neutrophil influx in bronchoalveolar lavage fluid.

OBJECTIVE: Study of leukocyte activation and release of toxic mediators during extracorporeal circulation (ECC). ECC can be used to study the potential protective effect of a pharmacon against neutrophil-mediated lung injury. Clinical studies have indicated that N-acetylcysteine (NAC) may improve systemic oxygenation and reduce the need for ventilatory support when given to patients with acute lung injury. DESIGN: Cardiac surgery patients were pretreated with high-dose NAC in order to assess the potential role of NAC to interfere with neutrophil-mediated inflammation and lung injury. PATIENTS: 18 patients who underwent ECC: group 1 (n = 8) no premedication (only placebo); group 2 (n = 10) NAC (72 mg/kg i.v. as a bolus, later 72 mg/kg over 12 h). MEASUREMENTS AND RESULTS: In group 2, the partial pressure of oxygen in arterial blood/fractional inspired oxygen 4 h after surgery was significantly higher than in group 1 (213 +/- 31 vs 123 +/- 22; p = 0.044). NAC pretreatment prevented an increase in plasma neutrophil elastase activity (18.9 +/- 6.9 vs 49.9 +/- 5.6 ng/ml in group 1 at the end of ECC; p = 0.027). Release of myeloperoxidase (MPO) was not affected (group 1:1105 +/- 225 ng/ml vs group 2:1127 +/- 81 at the end of ECC; p = 0.63). At the end of ECC, total antigenic human neutrophil elastase (group 1:671 +/- 72 ng/ml vs group 2:579 +/- 134; p = 0.37) and complex formation between elastase and alpha 1-proteinase inhibitor were no different in the two groups. There were no significant difference in cellular composition and mediators in the lavage fluid, although values for total number of neutrophils, elastase, MPO and interleukin-8 were lower in group 2. CONCLUSION: Pretreatment with NAC may prevent lung injury by diminishing elastase activity. Since the release of mediators, especially MPO, is not affected, this diminished activity of elastase may be achieved by enhanced inactivation by antiproteases after initial treatment.

The inflammatory marker serum eosinophil cationic protein (ECP) compared with PEF as a tool to decide inhaled corticosteroid dose in asthmatic patients.

The objective of this study was to compare the inflammatory marker eosinophil cationic protein (ECP) with peak expiratory flow (PEF) in determining the therapeutic needs of inhaled corticosteroids in asthma patients assessed as asthma symptoms. A randomized, single-blind study over 6 months was performed at six specialist centres in Europe. In total, 164 adult patients with moderate to severe symptomatic asthma and regular use of inhaled corticosteroids were included. After a run-in period of 2 weeks patients were randomly allocated to the ECP or the PEF monitoring group. The dose of inhaled cort costeroids was adjusted every fourth week based on the current serum ECP value or pre-bronchodilator morning PEF values as surrogate markers of therapeutic needs. At the end of the study there were no statistically significant differences in the mean daily symptom score or the percentage of symptom-free days between the two groups. The mean daily dose of inhaled corticosteroids was similar in the two groups at the start of the study but the algorithms used to adjust the dose of inhaled corticosteroids resulted in an increased use of inhaled corticosteroids in both groups. The mean daily dose of inhaled corticosteroids over the whole study period was significantly lower in the ECP group compared withthe PEF group (1246 vs. 1667 microg, P = 0.026). In the ECP group, forced expiratory volume in I sec (FEV)% predicted was lower at the end ofthe study compared with the begining (92% vs. 87%, P = 0 .0009), although there was no significant difference between the two groups. None of the used algorithms for ECP and PEF led to improvement in symptom scores, in spite of increased doses of inhaled corticosteroids. In this respect, both methods were equivalent and insufficient. Recommendations suggesting lung function tests in current guidelines may be difficult to translate into clinical practice, however, a combination of inflammatory markers, lung function and symptoms may still improve asthma control.

Metabolic disregulation in obese adolescents with sleep-disordered breathing before and after weight loss.

OBJECTIVE: Sleep-disordered breathing (SDB) is prevalent in obesity. Weight loss is one of the most effective treatment options. The aim was to assess the association of SDB and metabolic disruption before and after weight loss. DESIGN AND METHODS: Obese adolescents were included when entering an in-patient weight loss program. Fasting blood analysis was performed at baseline and after 4-6 months. Sleep screening was done at baseline and at follow-up in case of baseline SDB. RESULTS: 224 obese adolescents were included. Median age was 15.5 years (10.1-18.0) and mean BMI z-score was 2.74 ± 0.42. About 30% had SDB at baseline (N = 68). High-density lipoprotein (HDL)-cholesterol was associated with mean nocturnal oxygen saturation () (partial r = 0.21; P = 0.002). Aspartate aminotransferase (ASAT) and alanine aminotransferase were related with oxygen desaturation index (partial r = -0.15; P = 0.03 and partial r = -0.15; P = 0.02), but this became insignificant after correction for sex. After weight loss, 24% had residual SDB. Linear regression showed an association between ASAT and (partial r = -0.34; P = 0.002). There were no significant correlations between improvements in laboratory measurements and sleep parameters. HDL-cholesterol improved in relation with the decrease in BMI z-score. CONCLUSION: SDB at baseline was associated with higher levels of liver enzymes and lower HDL-cholesterol concentration. Improvements in sleep parameters were not associated with improvements in laboratory measurements.

Customizing systemic therapy in patients with advanced non-small cell lung cancer.

Lung cancer is the leading cause of cancer deaths worldwide. Standard chemotherapy has been shown to improve quality of life and has a modest influence on overall survival. This modest improvement in survival is partly due to the choice of chemotherapy regimens that have been based on prognostic factors such as age, performance status and comorbidities of the patient. This underlines the importance of developing a more personalized therapy for patients with non-small cell lung cancer. Such an approach may reduce the variation in how individual patients respond to medications by tailoring therapies to their genetic profile. In this review we focus on several aspects of customized therapy, looking not only at patient characteristics but also to tumor histology and specific tumor biomarkers.

Functional imaging using computer methods to compare the effect of salbutamol and ipratropium bromide in patient-specific airway models of COPD.

BACKGROUND: Salbutamol and ipratropium bromide improve lung function in patients with chronic obstructive pulmonary disease (COPD). However, their bronchodilating effect has not yet been compared in the central and distal airways. Functional imaging using computational fluid dynamics offers the possibility of making such a comparison. The objective of this study was to assess the effects of salbutamol and ipratropium bromide on the geometry and computational fluid dynamics-based resistance of the central and distal airways. METHODS: Five patients with Global Initiative for Chronic Obstructive Lung Disease Stage III COPD were randomized to a single dose of salbutamol or ipratropium bromide in a crossover manner with a 1-week interval between treatments. Patients underwent lung function testing and a multislice computed tomography scan of the thorax that was used for functional imaging. Two hours after dosing, the patients again underwent lung function tests and repeat computed tomography. RESULTS: Lung function parameters, including forced expiratory volume in 1 second, vital capacity, overall airway resistance, and specific airway resistance, changed significantly after administration of each product. On functional imaging, the bronchodilating effect was greater in the distal airways, with a corresponding drop in airway resistance, compared with the central airways. Salbutamol and ipratropium bromide were equally effective at first glance when looking at lung function tests, but when viewed in more detail with functional imaging, hyporesponsiveness could be shown for salbutamol in one patient. Salbutamol was more effective in the other patients. CONCLUSION: This pilot study gives an innovative insight into the modes of action of salbutamol and ipratropium bromide in patients with COPD, using the new techniques of functional imaging and computational fluid dynamics.

Pulmonary rehabilitation and non-invasive ventilation in COPD.

A multidisciplinary pulmonary rehabilitation program has become an important part of the treatment of chronic obstructive pulmonary disease. It can improve both exercise tolerance and health related quality of life in these patients. Exercise training has to be included for the program to be successful. The intensity of the training is of great importance: there is more physiological benefit in high-intensity training, compared to moderate-intensity training. High-intensity training results in reduced levels of blood lactate and pulmonary ventilation at a given heavy work rate. High-intensity training is limited in COPD patients because of exercise-induced dyspnoea. Flow limitation, as a consequence of increased ventilatory demands of exercise, causes a breathing pattern with greater demands on their inspiratory muscles: this results in a pattern of low tidal volume and high-frequency breathing. Increased inspiratory muscle work causes dyspnoea and limitation in exercise intensity. Artificial ventilatory assistance could improve exercise tolerance and hence help severe COPD patients to achieve a higher level of training. It could help to unload and assist the overburdened ventilatory muscles and give a possibility for higher levels of exercise intensity. In this review article we will discuss the effectiveness and feasibility of training with ventilatory aids.