EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.

BACKGROUND: Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality. AIM: Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology to critically evaluate the evidence regarding potential links and the impact of therapy. MATERIALS AND METHODS: Thirteen research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 were included. Statements were generated regarding current evidence and clinical practice. RESULTS: Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, whilst CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, whilst the pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, whilst treatment data are scarce. DISCUSSION/CONCLUSION: Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.

Adipose tissue in obesity and obstructive sleep apnoea.

A European Respiratory Society research seminar on "Metabolic alterations in obstructive sleep apnoea (OSA)" was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA. Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models or in vitro systems. Since most OSA patients are obese, their management requires a multidisciplinary approach. This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children. Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.

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 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.

Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome?

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disease and is recognised as a major public health burden. Large-scale epidemiological studies have demonstrated an independent relationship between OSAS and various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood but a multifactorial aetiology is likely. Inflammatory processes have emerged as critical in the pathogenesis of atherosclerosis at all stages of atheroma formation. Increased levels of various circulating markers of inflammation including tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL6), IL-8 and C-reactive protein (CRP) have been reported as associated with future cardiovascular risk. There is increasing evidence of elevated inflammatory markers in OSAS with a significant fall after effective treatment with continuous positive airway pressure. This evidence is particularly strong for TNFalpha, whereas studies on IL6 and CRP have yielded conflicting results possibly due to the confounding effects of obesity. Cell culture and animal studies have significantly contributed to our understanding of the underlying mechanisms of the association between OSAS and inflammation. Intermittent hypoxia, the hallmark of OSAS, results in activation of pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kappaB) and activator protein (AP)-1. These promote activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory mediators that may lead to endothelial dysfunction. This review provides a critical analysis of the current evidence for an association between OSAS, inflammation and cardiovascular disease, discusses basic mechanisms that may be responsible for this association and proposes future research possibilities.

Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation.

There is increasing evidence that intermittent hypoxia plays a role in the development of cardiovascular risk in obstructive sleep apnoea syndrome (OSAS) through the activation of inflammatory pathways. The development of translational models of intermittent hypoxia has allowed investigation of its role in the activation of inflammatory mechanisms and promotion of cardiovascular disease in OSAS. There are noticeable differences in the response to intermittent hypoxia between body tissues but the hypoxia-sensitive transcription factors hypoxia-inducible factor-1 and nuclear factor-kappaB appear to play a key role in mediating the inflammatory and cardiovascular consequences of OSAS. Expanding our understanding of these pathways, the cross-talk between them and the activation of inflammatory mechanisms by intermittent hypoxia in OSAS will provide new avenues of therapeutic opportunity for the disease.

Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome?

Obstructive sleep apnoea syndrome (OSAS) is a highly prevalent disease and is recognised as a major public health burden. Large-scale epidemiological studies have demonstrated an independent relationship between OSAS and various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood but a multifactorial aetiology is likely. Inflammatory processes have emerged as critical in the pathogenesis of atherosclerosis at all stages of atheroma formation. Increased levels of various circulating markers of inflammation including tumour necrosis factor alpha (TNFalpha), interleukin 6 (IL6), IL-8 and C-reactive protein (CRP) have been reported as associated with future cardiovascular risk. There is increasing evidence of elevated inflammatory markers in OSAS with a significant fall after effective treatment with continuous positive airway pressure. This evidence is particularly strong for TNFalpha, whereas studies on IL6 and CRP have yielded conflicting results possibly due to the confounding effects of obesity. Cell culture and animal studies have significantly contributed to our understanding of the underlying mechanisms of the association between OSAS and inflammation. Intermittent hypoxia, the hallmark of OSAS, results in activation of pro-inflammatory transcription factors such as nuclear factor kappa B (NF-kappaB) and activator protein (AP)-1. These promote activation of various inflammatory cells, particularly lymphocytes and monocytes, with the downstream consequence of expression of pro-inflammatory mediators that may lead to endothelial dysfunction. This review provides a critical analysis of the current evidence for an association between OSAS, inflammation and cardiovascular disease, discusses basic mechanisms that may be responsible for this association and proposes future research possibilities.

Medico-legal implications of sleep apnoea syndrome: driving license regulations in Europe.

BACKGROUND: Sleep apnoea syndrome (SAS), one of the main medical causes of excessive daytime sleepiness, has been shown to be a risk factor for traffic accidents. Treating SAS results in a normalized rate of traffic accidents. As part of the COST Action B-26, we looked at driving license regulations, and especially at its medical aspects in the European region. METHODS: We obtained data from Transport Authorities in 25 countries (Austria, AT; Belgium, BE; Czech Republic, CZ; Denmark, DK; Estonia, EE; Finland, FI; France, FR; Germany, DE; Greece, GR; Hungary, HU; Ireland, IE; Italy, IT; Lithuania, LT; Luxembourg, LU; Malta, MT; Netherlands, NL; Norway, EC; Poland, PL; Portugal, PT; Slovakia, SK; Slovenia, SI; Spain, ES; Sweden, SE; Switzerland, CH; United Kingdom, UK). RESULTS: Driving license regulations date from 1997 onwards. Excessive daytime sleepiness is mentioned in nine, whereas sleep apnoea syndrome is mentioned in 10 countries. A patient with untreated sleep apnoea is always considered unfit to drive. To recover the driving capacity, seven countries rely on a physician's medical certificate based on symptom control and compliance with therapy, whereas in two countries it is up to the patient to decide (on his doctor's advice) to drive again. Only FR requires a normalized electroencephalography (EEG)-based Maintenance of Wakefulness Test for professional drivers. Rare conditions (e.g., narcolepsy) are considered a driving safety risk more frequently than sleep apnoea syndrome. CONCLUSION: Despite the available scientific evidence, most countries in Europe do not include sleep apnoea syndrome or excessive daytime sleepiness among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable.

Biomechanical evaluation of a non-locking pre-manufactured loop suture technique compared to a three-loop pulley suture in a canine calcaneus tendon avulsion model.

OBJECTIVE: The purpose of this cadaveric study was to compare the strength of a non-locking pre-manufactured loop (SpeedWhip™ [SW]) suture pattern using Fiberwire® with the three-loop pulley (TLP) suture pattern using polypropylene for the surgical repair of canine calcaneal tendon avulsion injuries. METHODS: In vitro biomechanical study using 22 paired tendons collected from 11 canine cadavers. Paired tendons were repaired with either a SW suture pattern using Fiberloop® suture or a TLP suture pattern using polypropylene suture. Tensile loads required to create a 1 mm gap, 3 mm gap, and construct failure were measured. RESULTS: The mean loads to achieve a 1 mm gap in the TLP and SW constructs were not significantly different. Gap formation at 3 mm occurred at significantly lower loads for the SW (106.4 ± 21.5N) than for the TLP (127.2 ± 27.5N) (p = 0.05). The mean loads to construct failure for the TLP (172.8 ± 39.4N) and SW (131.3 ± 34.3N) were significantly different (p = 0.001). CLINICAL SIGNIFICANCE: The TLP with polypropylene suture is superior to the SW using Fiberloop® at resistance to 3 mm gap formation.

Home mechanical ventilation.

A postal survey assessed the role of home mechanical ventilators (HMV) in the management of chronic respiratory failure in the Irish Republic. The survey collected information on indications for therapy, investigations performed and patient follow-up. Surveys were sent to all centres identified as prescribing HMV and were completed by February 2002, relating to the situation existing on July 1st 2001. From a total of 52 preliminary surveys, 14 centres (including two paediatric) were identified as prescribing HMV. A total of 157 patients used HMV and 67 (43%) were initiated on HMV during the 12 months prior to the survey. There were more males than females (86[55%] v 71[45%]) and most (61%) were in the 25-65 age bracket. The causes of respiratory failure were lung diseases (41%), thoracic cage deformities (33%), and neuromuscular diseases (26%). The majority of HMV users (95%) were prescribed pressure-cycled ventilators. The survey identified inadequate procedures for follow-up of patients on HMV and an over-reliance on equipment suppliers for patient support.

Disordered breathing during sleep and exercise in idiopathic pulmonary fibrosis and the role of biomarkers.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) patients report fatigue, possibly reflecting sleep disturbance, but little is known about sleep-related changes. We compared ventilation and gas exchange during sleep and exercise in a cohort of IPF patients, and evaluated associations with selected biological markers. METHODS: Twenty stable IPF patients (aged 67.9 ± 12.3 [SD]) underwent overnight polysomnography following an acclimatization night. Cardiopulmonary exercise testing was performed and inflammatory markers measured including TNF-α, IL-6, CXCL8, C-C motif ligand 18 (CCL-18) and C-reactive protein (CRP) RESULTS: Nine patients had sleep-disordered breathing (SDB) with an apnea-hypopnea frequency (AHI) ≥ 5/h, but only two had Epworth sleepiness score ≥ 10, thus having an obstructive sleep apnea syndrome. Sleep quality was poor. Transcutaneous carbon dioxide tension (PtcCO2) rose by 2.56 ± 1.59 kPa overnight (P = 0.001), suggesting hypoventilation. Oxygen saturation (SaO2) was lower during sleep than exercise (P < 0.01), and exercise variables correlated with resting pulmonary function. CCL-18 and CRP levels were elevated and correlated with PtcCO2 rise during sleep (P < 0.05). CCL-18 negatively correlated with diffusion capacity of carbon monoxide (DLCO), arterial oxygen (PaO2) and mean arterial carbon dioxide (PaCO2) (P < 0.05) and CRP negatively correlated with DLCO, PaO2, sleep SaO2 and oxygen uptake (VO2) during exercise (P < 0.05). CONCLUSIONS: IPF patients desaturate more during sleep than exercise; thus, nocturnal pulse oxymetry could be included in clinical assessment. CCL-18 and CRP levels correlate with physiological markers of fibrosis.

New chemotherapy combinations with docetaxel in the treatment of patients with non-small cell lung cancer.

The modest antitumor activity and clinical benefit of conventional platinum-containing multidrug regimens in locally advanced and metastatic non-small cell lung cancer have provided the impetus for the development of novel combinations. The promising single-agent activity of docetaxel makes it an obvious candidate for incorporation into active programs. The Irish Clinical Oncology Research Group is conducting a phase I-II evaluation of a three-drug combination of docetaxel, ifosfamide, and cisplatin with lenograstim support in patients with stages III-IV non-small cell lung cancer. Preliminary results indicate that the regimen is feasible and tolerable up to a maximum tolerated dose level of 3,000 mg/m2 ifosfamide, 75 mg/m2 cisplatin, and 75 mg/ m2 docetaxel. The regimen appears to be quite active, with nine of 12 evaluable patients responding in the phase I component of the trial. This dose level is currently being explored in a phase II trial.

Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis.

PURPOSE: Hypercapnia is regarded as a poor prognostic indicator in chronic obstructive pulmonary disease (COPD), but many patients hospitalized with hypercapnia associated with an acute exacerbation of COPD revert to normocapnia during recovery. We wished to determine if this reversible hypercapnia represents a distinct pattern of respiratory failure in COPD, or simply a stage in the progression to chronic hypercapnia. We therefore compared the long-term clinical progression and survival of COPD patients with reversible hypercapnic respiratory failure (defined as type 2.1) to those with normocapnic (PaCO2 < 50 mm Hg; type 1) and also to those patients with chronic hypercapnic (PaCO2 > 50 mm Hg) respiratory failure (defined as type 2.2). PATIENTS AND METHODS: We prospectively followed for 5 years a cohort of 85 patients who had been admitted as emergencies during a 1-year period to the respiratory unit of a University teaching hospital with an exacerbation of COPD complicated by respiratory failure (PaO2 < 60 mm Hg). The main long-term outcome measures were survival and blood gas changes. RESULTS: Sixty-eight (80%) patients survived the initial admission, and 17 (27%) survived 5 years. PaCO2 rose substantially more during exacerbations in type 2.1 patients (mean 15.8 mm Hg), compared with type 2.2 (mean 6.8 mm Hg) and type 1 patients (mean 1.5 mm Hg). We analyzed 149 subsequent admissions among the survivors over the following 5 years. Type 2.1 patients had a better 5-year survival (28%) than type 2.2 (11% survival; P < 0.05), and similar to type 1 patients (33% 5-year survival). Only 24% of reversible hypercapnic patients developed chronic hypercapnia during long-term followup. CONCLUSIONS: The data support reversible hypercapnia being a distinct manifestation of respiratory failure in COPD, with a similar prognosis to that of normocapnic respiratory failure.

Obstructive sleep apnea syndrome: who should be treated?

Most, if not all patients referred for assessment require some form of therapeutic intervention. In particular, general lifestyle advice, sleep hygiene, and weight reduction in overweight patients should always be promoted, even where additional specific therapy such as NCPAP is also being considered. Treatment decisions are relatively easy at the extremes of the clinical spectrum, but there is an increasing choice of therapeutic options available for those patients in the mid-range of severity. Criteria based on AHI levels are inappropriate to dictate treatment choice, particularly NCPAP.

Clinical prediction of the sleep apnea syndrome.

Polysomnography, the standard diagnostic test for people suspected of having sleep apnea, is a limited resource due to its expense. Decisions about which patients to refer to a sleep center and which require polysomnography can be made based on an estimate of the probability that they have sleep apnea. Clinical features that are associated with the severity of sleep apnea, as judged by the apnea-hypopnea index, can be combined together using statistical modeling into a clinical prediction rule, whose diagnostic performance can be summarized by its sensitivity and specificity or by likelihood ratios. To date, at least seven different sleep apnea clinical prediction rules have been developed, most incorporate anthropomorphic variables such as the body mass index, waist circumference, and/or neck circumference, and some type of abnormal respiration during sleep (snoring, apneas, choking and/or gasping) witnessed by a bed partner. In general these rules have reasonably high sensitivities but only intermediate specificities, thus they can be useful in excluding the diagnosis but do not usually raise the probability of sleep apnea high enough to warrant initiating therapy without at least some type of additional testing to confirm the diagnosis. In isolation the apnea-hypopnea index is not an optimal indicator of disease severity, thus ultimately clinical decisions about the need for polysomnography and/or the need for treatment must take into account other important clinical information such as symptom severity, quality of life, and the presence or absence of comorbid illness.

Impact of sleep in COPD.

Sleep has well-recognized effects on breathing, including changes in central respiratory control, airways resistance, and muscular contractility, which do not have an adverse effect in healthy individuals but may cause problems in patients with COPD. Sleep-related hypoxemia and hypercapnia are well recognized in COPD and are most pronounced in rapid eye movement sleep. However, sleep studies are usually only indicated in patients with COPD when there is a possibility of sleep apnea or when cor pulmonale and/or polycythemia are not explained by the awake PaO(2) level. Management options for patients with sleep-related respiratory failure include general measures such as optimizing therapy of the underlying condition; physiotherapy and prompt treatment of infective exacerbations; supplemental oxygen; pharmacologic treatments such as bronchodilators, particularly ipratropium bromide, theophylline, and almitrine; and noninvasive positive pressure ventilation.

Theophylline in obstructive sleep apnea. A double-blind evaluation.

Twelve patients with documented obstructive sleep apnea were enrolled in a double-blind placebo controlled crossover trial of oral theophylline, (Uniphyllin) 800 mg, taken at night for four weeks. Overnight polysomnography, using standard techniques, was performed at the end of each treatment period. The total number of apneas (A) and hypopneas (H) decreased significantly while receiving theophylline compared to placebo, from 398 (69), mean (SEM), to 283 (72), p less than 0.01. Sleep quality was, however, significantly worse while receiving theophylline. Obstructive A and H were very much decreased with theophylline (p less than .001), and even when the data were adjusted for the more disturbed sleep with theophylline, this decrease remained significant; the obstructive A and H index fell from 49 (8.7) on placebo to 40 (9) while receiving theophylline, p = 0.02. There was no difference in the numbers of central or mixed A and H, and mean A and H duration was unchanged on the two study nights. Oxygen desaturations greater than 4 percent were less with theophylline treatment (p = 0.02), but mean overnight SaO2 was unchanged. We conclude that theophylline may be beneficial in patients with OSA, but part of the improvement is due to a deterioration in sleep quality.

Ventilation and gas exchange during sleep and exercise in severe COPD.

Ventilation and gas exchange were studied during sleep and incremental treadmill exercise in 19 patients with severe stable COPD with the primary aim of comparing the pathophysiology of oxygen desaturation in the two conditions. A secondary aim was to determine whether exercise studies could aid in the prediction of sleep desaturation. Full polysomnography was used, and ventilation, arterial oxygen saturation (SaO2), and transcutaneous PCO2 (PtcCO2) were monitored continuously during sleep. No patient had significant sleep apnea. Mean (SD) FEV1 was 32 (9.1)% predicted, PaO2 was 71.2 (12.4) mm Hg, and PaCO2 was 44.5 (4.6) mm Hg. SaO2 fell twice as much during sleep as during maximum exercise: 13.1 (8.9) vs 6.0 (3.6)% (p < 0.001). The mean sleep and exercise SaO2, and minimum sleep and exercise SaO2 were well correlated on linear regression (r = 0.81 and 0.78, respectively, p < 0.001), but on multiple regression analysis, awake PaO2 was a better predictor of sleep desaturation than was exercise desaturation. The 12 major desaturators (minimum sleep SaO2 < 85%) had twice as great a fall in exercise SaO2 as the 7 minor desaturators (3.6 +/- 2.8 vs 7.4 +/- 3.3%, p < 0.05). The major desaturators also had a greater fall in estimated sleep PaO2: 19.8 (5.1) vs 6.4 (7.1) mm Hg (p < 0.01), which suggests that their greater sleep desaturation is not simply due to their position on the steep portion of the oxyhemoglobin dissociation curve. The rise in PtcCO2 during sleep was similar among major and minor desaturators: 7.5 (2.9) vs 5.8 (3.7) mm Hg (p = NS), suggesting that all patients had a similar degree of hypoventilation during sleep, and that the greater fall in SaO2 and estimated PaO2 among some patients was secondary to other factors such as increased ventilation-perfusion mismatching.