W. De Backer

Increased prevalence of sleep disturbances and daytime sleepiness in subjects with bronchial asthma: a population study of young adults in three European Countries.

The aim of this study was to investigate whether asthma is associated with decreased quality of sleep and increased daytime sleepiness. The study involved a random population of 2,202 subjects supplemented by 459 subjects with suspected asthma, aged 20-45 yrs. The subjects were from Reykjavik (Iceland), Uppsala and Göteborg (Sweden) and Antwerp (Belgium), and participated in the European Community Respiratory Health Survey. The investigation included a structured interview, methacholine challenge, skinprick tests and a questionnaire on sleep disturbances. Participants in Iceland and Sweden also estimated their sleep times and made peak expiratory flow (PEF) recordings during a period of 1 week. Asthma was defined as self-reported physician-diagnosed asthma with current asthma-related symptoms (n = 267). Difficulties inducing sleep (DIS) and early morning awakenings (EMA) were about twice as common, and daytime sleepiness 50% more common, in asthmatics compared with subjects without asthma. After adjusting for possible confounders, a positive association was found between asthma and: DIS (odds ratio (OR) = 1.8); EMA (OR = 2.0); daytime sleepiness (OR = 1.6); snoring (OR = 1.7); and self reported apnoeas (OR = 3.7). Allergic rhinitis, which was reported by 71% of subjects with asthma, was independently related to DIS (OR = 2.0) and daytime sleepiness (OR = 1.3). A significant correlation was found between the number of asthma-related symptoms and sleep disturbances (p < 0.001). Asthma is associated with decreased subjective quality of sleep and increased daytime sleepiness. Concurrent allergic rhinitis may be an important underlying cause of sleep impairment in asthmatic patients.

Potential role of Clara cell protein, an endogenous phospholipase A2 inhibitor, in acute lung injury

It is now recognized that epithelial cells lining airways and alveoli are capable of releasing various mediators, which have the potential to modulate local inflammatory reactions. The amount of the 16 kDa Clara cell protein (CC16), an inhibitor of phospholipase A2 activity produced by pulmonary epithelial cells, was measured by means of a sensitive immunoassay in the unconcentrated bronchoalveolar lavage fluid (BALF) of 13 control subjects, and in patients with acute lung injury (14 with the full-blown adult respiratory distress syndrome (ARDS); 21 after standard cardiopulmonary bypass surgery, a known risk factor for ARDS). The level of CC16 was compared with other markers of inflammation with a wide range of molecular weights: albumin (nephelometry); total protein (spectrophotometry); beta 2-microglobulin (latex immunoassay); cystatin C (latex immunoassay); alpha 1-antitrypsin (immunoradiometry), and lipocortin-1 (enzyme-linked immunosorbent assay (ELISA)). The Clara cell protein (CC16) was detectable in all BALF, and significantly higher levels of this protein were observed in BALF from patients with acute lung injury. Changes in BALF Clara cell protein levels differed from those of alpha 2-macroglobulin and the natural phospholipase inhibitor lipocortin-1. Alpha 2-macroglobulin levels were not significantly enhanced in patients at risk for ARDS, but were increased in patients with ARDS; whereas, lipocortin 1 levels were not elevated in either group. Pretreatment of patients at risk for ARDS with high dose methylprednisolone did not alter the amount of Clara cell protein recovered in BALF. The mean CC16 level in BALF from patients with ARDS who died was significantly lower than from those who survived. The data presented in this study suggest that pulmonary epithelial cells secrete a natural anti-inflammatory protein during acute lung injury, which might have a protective and immunosuppressive role.

Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer

Despite technical difficulties due to mediastinal fibrosis, remediastinoscopy can be a valuable tool in the restaging of non-small cell lung cancer after neoadjuvant therapy. The aim of our study was to evaluate the feasibility, sensitivity and accuracy of remediastinoscopy. From November 1994 to July 2001 we performed a remediastinoscopy in 27 patients after neoadjuvant therapy. Their age ranged from 35 to 80 years (mean 61.9+/-11.9). In all 27 patients it was possible to perform a remediastinoscopy without major technical difficulties and take biopsies of the lymph nodes that were initially invaded by tumour. Remediastinoscopy was positive in 11 patients (40.7%) and negative in 16 (59.3%). In the 11 patients with a positive remediastinoscopy a complete resection was not judged possible and therefore, an unnecessary thoracotomy was avoided. In four patients, remediastinoscopy turned out to be false negative. So, in our series, sensitivity was 73%, specificity 100% and accuracy 85%. The positive and negative predictive values were 100 and 75%, respectively. Previous mediastinoscopy is no contra-indication for a repeat one after neoadjuvant therapy. Although sensitivity and accuracy are lower than that of a first mediastinoscopy, remediastinoscopy is useful to select patients for surgical resection after induction therapy.

Evaluation for sleep apnea in patients with Ehlers-Danlos syndrome and Marfan: a questionnaire study

Sleep complaints are frequently reported by patients with Marfan and Ehlers–Danlos syndrome (EDS). We examined the exact nature of sleep complaints in these patients. 
A representative sample of Marfan and EDS patients responded to a general sleep questionnaire, including the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study Short‐Form 36 (SF‐36) health‐related quality of life (QOL) questionnaire. Fifteen Marfan patients and 9 EDS patients were evaluated and compared to 24 healthy controls, matched for age, sex and body mass index. Maintaining sleep was frequently disturbed in Marfan (40%, p<0.04) as well as in EDS patients (56%, p<0.01). 
Sleep apnea was exclusively reported by Marfan patients (27%, p=0.03). Periodic limb movements were much more reported in EDS (67%, p=0.02) than in Marfan (27%, p=0.25) compared to controls (8%). Pain and back complaints were highly presented in both groups, but most pronounced in EDS patients (47% in Marfan versus 77% in EDS). No differences for the scores in the ESS were found. For all SF‐36 questionnaire items, scores were much lower in patient groups, except for emotional problems. We found that sleep complaints were not rare in Marfan and EDS patients and correlated well with different QOL items. Our study calls for greater attention to the presence of apnea, pain and periodic limb movements in these patients.

The European sleep apnoea database (ESADA) –report from 22 European sleep laboratories

The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 program. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5103 patients (1426 females, age 51.8±12.6 years, 79.4% with AHI≥5 events·hr−1) were included from March 15, 2007 to August 1, 2009. Morbid obesity (BMI≥35 kg·m−2) was present in 21.1% of males and 28.6% of women. Cardiovascular, metabolic, and pulmonary comorbidities were frequent (49.1, 32.9 and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 vs. 29.1±26.3 events·hour−1, p<0.0001). The ESADA is a rapidly growing multicentric patient cohort that enables unique outcome research opportunities and genotyping. The first cross sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSAS.The European Sleep Apnoea Database (ESADA) reflects a network of 22 sleep disorder centres in Europe enabled by a COST action B26 programme. This ongoing project aims to describe differences in standard clinical care of patients with obstructive sleep apnoea (OSA) and to establish a resource for genetic research in this disorder. Patients with suspected OSA are consecutively included and followed up according to local clinical standards. Anthropometrics, medical history, medication, daytime symptoms and sleep data (polysomnography or cardiorespiratory polygraphy) are recorded in a structured web-based report form. 5,103 patients (1,426 females, mean±sd age 51.8±12.6 yrs, 79.4% with apnoea/hypopnoea index (AHI) ≥5 events·h−1) were included from March 15, 2007 to August 1, 2009. Morbid obesity (body mass index ≥35 kg·m−2) was present in 21.1% of males and 28.6% of females. Cardiovascular, metabolic and pulmonary comorbidities were frequent (49.1%, 32.9% and 14.2%, respectively). Patients investigated with a polygraphic method had a lower AHI than those undergoing polysomnography (23.2±23.5 versus 29.1±26.3 events·h−1, p<0.0001). The ESADA is a rapidly growing multicentre patient cohort that enables unique outcome research opportunities and genotyping. The first cross-sectional analysis reveals a high prevalence of cardiovascular and metabolic morbidity in patients investigated for OSA.

Central sleep apnoea, pathogenesis and treatment: an overview and perspective

The prevalence of reported sleep disturbances in a general population is high. Many of the complaints are the result of sleep-related breathing disorders, due mainly to the occurrence of obstructive and central apnoeas. Obstructive sleep apnoea is a fully described and well-recognized entity. Central sleep apnoea (CSA) however, has been poorly studied. There is accumulating evidence that central sleep apnoea should be considered as the end of a spectrum. Instability in the breathing pattern is the main underlying mechanism and is due to the interaction of many factors. Breathing during sleep is dependent on metabolic control and the activity of the respiratory muscles. Decreased chemical drive and/or failing respiratory muscle function are associated with CSA and usually also with ongoing hypoventilation during wakefulness, characterized by chronic daytime hypercapnia. Central respiratory drive can also be inhibited by upper airway reflexes. Mostly, however, CSA occurs as the hallmark of unstable breathing during sleep brought about by an overall increase in loop gain (especially in light sleep stages) and the unmasking of a CO2 threshold. Arousal following central apnoeas acts as an amplification of the instability. Micro electroencephographic (EEG) arousals are often observed as a consequence of CSA. They are responsible for sleep fragmentation and hypersomnolence during the day. The daytime hypersomnolence and complaints of awakenings during sleep in patients with CSA can be striking. CSA can occur in specific pathologies, such as chronic heart failure and (post-traumatic) brain lesions, that are associated with irregular breathing. Treatment strategies are remarkably few in number. Use of nasal ventilation and the inhalation of CO2 are mainly of theoretical interest, since patients do not often tolerate these more invasive therapies. Drug treatment, especially with acetazolamide, is easier to perform. Stimulation of upper airway reflexes, by less invasive methods, seems to be promising for the near future.

Site of upper airway obstruction in obstructive apnoea and influence of sleep stage.

Various sites along the upper airway (UA) are prone to narrow and collapse in patients affected by obstructive sleep apnoea. Sleep stages may eventually alter these sites. The present study was designed to determine the site(s) of UA obstruction and the influence of sleep stage on the pattern of obstruction. Twenty eight obstructive sleep apnoea patients underwent UA pressure measurements during polysomnography. Solid-state pressure sensors were located at the nasopharynx, oropharynx, tongue base, hypopharynx and oesophagus and the lower limit of UA obstruction was determined relying on the observed pressure pattern. The site of UA obstruction varied among consecutive apnoeas in all but two patients. The lower limit of UA obstruction was predominantly located at the nasoand oropharynx. Rapid eye movement (REM) sleep was associated with a tendency for obstruction to extend towards lower levels of the UA and nasopharyngeal occlusion was significantly less observed during REM compared to oropharyngeal obstruction. Upper airway obstruction involves more than one specific site of the upper airway in the majority of sleep apnoea patients. Obstruction at lower levels of the upper airway is more likely to be observed during rapid eye movement sleep.

Lung function and bronchodilator response in 4-year-old children with different wheezing phenotypes

Persistent wheeze is a common chronic disease in early childhood and later may progress to asthma. However, the association between pre- and post-bronchodilator lung function and the wheezing phenotype in preschool children is not known. Children 4 yrs of age involved in a prospective birth cohort study (in Antwerp, Belgium) concerning perinatal factors and the occurrence of asthma and allergies, were invited to participate in lung function measurements with the forced oscillation technique. The wheezing phenotype was assessed via (bi)annual questionnaires. Wheezing phenotype and baseline respiratory impedance data were available for 325 children, 96% of whom underwent bronchodilation tests. The baseline resistance at 4 Hz was higher in children with early transient (11.0 hPa·s·L−1, n = 127) or persistent wheeze (11.9 hPa·s·L−1, n = 54) than in children who never wheezed (10.3 hPa·s·L−1, n = 144). After bronchodilation, the resistance decreased on average by 22%. The decrease was greater among the persistent wheezers than among those who never wheezed (3.4 versus 2.3 hPa·s·L−1). The baseline lung function was poorer and the bronchodilator response was greater in 4-yr-old children with persistent wheeze than in those who never wheeze or who had early transient wheeze, implying a higher bronchomotor tone in the former group.

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

ObjectiveStudy 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.DesignCardiac 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.Patients18 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 resultsIn 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 α1-proteinase inhibitor were no different in the two groups. There were no significant differences 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.ConclusionPretreatment 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.

Management of obstructive sleep apnea in Europe

OBJECTIVES In Europe, the services provided for the investigation and management of obstructive sleep apnoea (OSA) varies from country to country. The aim of this questionnaire-based study was to investigate the current status of diagnostic pathways and therapeutic approaches applied in the treatment of OSA in Europe, qualification requirements of physicians involved in diagnosis and treatment of OSA, and reimbursement of these services. METHODS Two questionnaires were sent to 39 physicians in 22 countries in Europe. In order to standardize the responses, the questionnaire was accompanied by an example. RESULTS Sleep centers from 21 countries (38 physicians) participated. A broad consistency among countries with respect to the following was found: pathways included referral to sleep physicians/sleep laboratories, necessity for objective diagnosis (primarily by polysomnography), use of polygraphic methods, analysis of polysomnography (PSG), indications for positive airway pressure (PAP) therapy, application of standard continuous PAP (CPAP) therapy (100% with an CPAP/APAP ratio of 2.24:1), and the need (90.5%) and management of follow-up. Differences were apparent in reimbursement of the diagnostic procedures and follow-up, in the procedures for PAP titration from home APAP titration with portable sleep apnea monitoring (38.1%) up to hospital monitoring with PSG and APAP (85.7%), and in the qualification requirements of sleep physicians. CONCLUSIONS Management of OSA in different European countries is similar except for reimbursement rules, qualification of sleep specialists and procedures for titration of the CPAP treatment. A European network (such as the one accomplished by the European Cooperation in Science and Technology [COST] B26 Action) could be helpful for implementing these findings into health-service research in order to standardize management in a cost effective perspective.