Role of the cardio-pulmonary exercise test and six-minute walking test in the evaluation of exercise performance in patients with late-onset Pompe disease.

In patients with late-onset Pompe disease, we explored the role of the Cardiopulmonary Exercise Test (CPET) and the Six-Minute Walking Test (6MWT) in the assessment of exercise capacity and in the evaluation of the effects of enzyme replacement therapy (ERT). Eight patients affected by late-onset Pompe disease, followed up at the Centre for Neuromuscular Diseases and treated with ERT, underwent a baseline evaluation with a spirometry, a CPET and a 6MWT. Four of them were restudied after 36 months of treatment. Three patients showed a reduction in exercise capacity as evaluated by peak oxygen uptake (VO2) measured at the CPET and Distance Walked (DW) measured at the 6MWT (median % predicted: 67.1 [range 54.3-99.6] and 67.3 [56.6-82.6], respectively). Cardiac and respiratory limitations revealed by the CPET were correlated to peak VO2, but not to the DW. Nevertheless, percent of predicted values of peak VO2 and DW were strongly correlated (rho = 0.85, p = 0.006), and close to identity. In the longitudinal evaluation forced vital capacity decreased, while peak VO2 and DW showed a trend to a parallel improvement. We concluded that although only the CPET revealed causes of exercise limitation, which partially differed among patients, CPET and 6MWT showed a similar overall degree of exercise impairment. That held true in the longitudinal assessment during ERT, where both tests demonstrated similar small improvements, occurring despite deterioration in forced vital capacity.

Successful treatment of atelectasis with Dornase alpha in a patient with congenital muscular dystrophy.

A 28-year-old neuromuscular patient chronically treated with nocturnal noninvasive ventilation developed pulmonary lobar atelectasis and daytime hypoxemia. Twenty four-hour 5L/min oxygen was begun, while mechanical cough assist aids were applied for seven days. In the following three days, treatment with nebulized Dornase alpha (rhDNase) b.i.d. was tested, without any significant improvement. On 11 and 13th days rhDNase was instilled by flexible bronchoscopy. A rapid resolution of the atelectasis was observed with relief of hypoxemia, without significant side effects. On day 16 the patient was discharged without oxygen requirements. In non-intubated neuromuscular patients with atelectasis who do not respond successfully to non-invasive treatments intrabronchial instillation of rhDNase may safely help to improve airway clearance.

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.

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.

High frequency chest wall oscillation plus mechanical in-exsufflation in Duchenne muscular dystrophy with respiratory complications related to pandemic Influenza A/H1N1.

Two young boys with Duchenne muscular dystrophy, who had contracted 2009 pandemic influenza A/H1N1 (pH1N1), had been treated with antibiotics and steroids without significant improvement. One of them showed severe scoliosis. After hospitalization chest CT scan revealed extensive pulmonary bilateral segmental atelectasis. Their clinical and radiological findings rapidly improved when a sequential respiratory physiotherapy protocol was adopted that consisted of the application of multiple sessions of high-frequency chest wall oscillations, each one followed by mechanically assisted coughing manoeuvres. The protocol was well tolerated, effective, easy to apply and special positioning was not required. Fifteen days after treatment initiation both patients clinically recovered. This treatment can be very helpful for neuromuscular patients, particularly when scoliosis prevents conventional respiratory physiotherapy.

Reticulocytes in untreated obstructive sleep apnoea.

BACKGROUND AND AIM: The short, repetitive hypoxaemic episodes observed in obstructive sleep apnoea (OSA) may determine small augmentations in mature red blood cells. It is unknown whether they affect reticulocyte release. This study explored whether the number and degree of maturation of circulating reticulocytes may be altered in OSA, possibly through the effect of erythropoietin. METHODS: Fifty male adult patients with suspected OSA, normoxic during wakefulness, were studied. After nocturnal polysomnography, a blood sample was withdrawn for blood cells count, erythropoietin, iron and transferrin determination. Reticulocyte concentration and degree of immaturity [high (H), medium (M), or low (L)] were also determined. Immature reticulocyte fraction (IRF) was calculated as (M+H) percentage of reticulocytes. RESULTS: A wide range of OSA severity was found [apnoea/hypopnoea index (AHI): 44.3 +/- 30.4, range 0.3-105; sleep time spent at oxyhaemoglobin saturation <90%: 18.1 +/- 22.2%, range 0-81%]. Both reticulocyte count and IRF slightly exceeded the normal range. Patients with a reticulocyte concentration > 2% had higher EPO levels (p < 0.05), but not worse nocturnal desaturations, than those with values < 2%. By contrast, subjects with IRF < 15% showed worse desaturations (p < 0.05), but similar EPO concentrations, when compared to subjects whose IRF was < 10%. At univariate analysis, reticulocyte count correlated to erythropoietin, while IRF to transferrin saturation, BMI and OSA severity. At multiple regression, only lowest nocturnal oxygen saturation remained a significant contributor to IRF (r2 0.223, p < 0.05). CONCLUSIONS: This data suggests that hypoxaemia due to OSA could influence the release of immature reticulocytes, but this effect is not mediated by erythropoietin.

Baroreflex control of heart rate during sleep in severe obstructive sleep apnoea: effects of acute CPAP.

Baroreflex control of heart rate during sleep (baroreflex sensitivity; BRS) has been shown to be depressed in obstructive sleep apnoea (OSA), and improved after treatment with continuous positive airway pressure (CPAP). Whether CPAP also acutely affects BRS during sleep in uncomplicated severe OSA is still debatable. Blood pressure was monitored during nocturnal polysomnography in 18 patients at baseline and during first-time CPAP application. Spontaneous BRS was analysed by the sequence method, and estimated as the mean sequence slope. CPAP did not acutely affect mean blood pressure or heart rate but decreased cardiovascular variability during sleep. Mean BRS increased slightly during CPAP application (from 6.5+/-2.4 to 7.5+/-2.9 ms x mmHg(-1)), mostly in response to decreasing blood pressure. The change in BRS did not correlate with changes in arterial oxygen saturation or apnoea/hypopnoea index. The small change in baroreflex control of heart rate during sleep at first application of continuous positive airway pressure in severe obstructive sleep apnoea was unrelated to the acute resolution of nocturnal hypoxaemia, and might reflect autonomic adjustments to positive intrathoracic pressure, and/or improved sleep architecture. The small increase in baroreflex control of heart rate during sleep may be of clinical relevance as it was accompanied by reduced cardiovascular variability, which is acknowledged as an independent cardiovascular risk factor.

Preference for fixed or automatic CPAP in patients with obstructive sleep apnea syndrome.

BACKGROUND: The aims of this study were to compare compliance to treatment with fixed CPAP and with autoCPAP, subjective preference for type of CPAP treatment, and factors associated to preference for autoCPAP in patients with OSAS. PATIENTS AND METHODS: Twenty-two subjects were studied in a randomized, single blind cross-over fashion. They were treated for one month by fixed CPAP (Elite Sullivan V, ResMed, Sydney, Australia) and one month by autoCPAP (Autoset T, ResMed, Sydney, Australia). RESULTS: Four subjects who stated a preference for fixed CPAP and four who expressed no preference were pooled together; fourteen preferred autoCPAP. Compliance to treatment using the two machines did not differ in the first group (3.8 (1.9) vs. 3.8 (1.5)h/day, fixed vs autoCPAP), but was higher with autoCPAP in the second group (4.8 (1.8) vs 5.5 (1.5)h/day, P<0.05). Baseline apnea/hypopnea index (AHI) was high in both groups, but was higher in the second group P<0.02. First treatment was always fixed CPAP in patients who preferred fixed CPAP, while it was either in the other subjects. CONCLUSIONS: Compliance to autoCPAP differs among OSAS patients. As long as factors predicting higher compliance to autoCPAP are not found, a trial with autoCPAP in patients poorly compliant to fixed CPAP may be warranted.

Effects of fixed compared to automatic CPAP on sleep in Obstructive Sleep Apnoea Syndrome.

BACKGROUND: Automatic CPAP has been developed to improve CPAP efficiency and compliance. Continually matching the effective pressure may be associated to more frequent arousals that could disturb sleep. The aim of the present study was to compare sleep architecture after one month's home therapy with CPAP or with an AutoCPAP device. METHODS: Twenty OSAS patients (18 M / 2 F) after polysomnographic study with CPAP titration received either an automatic (AutoSet T, ResMed, Sydney, Australia) or a fixed level CPAP machine in a random, single blind fashion for one month. At the end of the home treatment period polysomnography was repeated while CPAP was administered by the same machine used at home. RESULTS: There was no significant difference between groups in terms of age (50.0 vs 45.5, NS), sex, BMI (38.3 vs 35.1, NS), RDI (45.4 vs 48.0, NS), and CPAP effective level (9.8 vs 10.8, NS). After one month of therapy the correction of sleep respiratory disturbances and of sleep structure was satisfactory in both groups. No difference in any polysomnographic variable or in subjective sleepiness was found at re-evaluation. CONCLUSIONS: The results of this study demonstrate that on average CPAP administered by a fixed CPAP machine and by the AutoSet T autoCPAP device has similar effects in improving respiratory function during sleep, nocturnal sleep architecture, and subjective daytime sleepiness after a one-month therapy. As autoCPAP devices are more expensive than fixed CPAP machines, their prescription should be considered only after a clear demonstration of an increase in compliance to treatment by these devices.

Blood pressure responsiveness to obstructive events during sleep after chronic CPAP.

The aim of this study was to investigate whether chronic continuous positive airway pressure (CPAP) affects blood pressure (BP) responsiveness to obstructive events occurring on the first night of CPAP withdrawal in obstructive sleep apnoea (OSA) after chronic treatment. Thirteen male subjects with severe OSA underwent nocturnal polysomnography with beat-by-beat BP monitoring before treatment and after 4.9 +/- 3.4 months of home CPAP (mean daily use 5.1 +/- 1.7 h). Variations in oxyhaemoglobin saturation (deltaSa,O2), systolic (deltaPs), and diastolic (deltaPd) BP within nonrapid eye movement apnoeas and hypopnoeas were measured on a sample of pre- and post-treatment events. In addition, a pretreatment sample was selected for deltaSa,O2 to match post-treatment events. The higher the mean deltaSa,O2 was in the full pretreatment sample, the more deltaSa,O2, deltaPs and deltaPd were attenuated after treatment. Mean deltaPs decreased from 47.3 +/- 8.5 in the full pretreatment sample to 42.2 +/- 6.9 in the selected pretreatment sample, to 31.5 +/- 5.9 mmHg in the post-treatment sample. The post-treatment value differed significantly from both the pretreatment values. The corresponding values for mean deltaPd were 27.0 +/- 3.5, 24.0 +/- 3.1 and 19.6 +/- 3.7 mmHg, with all values differing significantly from each other. Chronic continuous positive airway pressure is followed by a decrease in apnoea/ hypopnoea-related blood pressure swings, possibly secondary to both reduced severity of event-related hypoxaemia and decreased responsiveness to obstructive events secondary to chronic prevention of nocturnal intermittent hypoxaemia.

Evaluation of the POLYMESAM system in the diagnosis of obstructive sleep apnea syndrome.

The reliability of a POLYMESAM (PM) instrument in the detection of ventilatory disorders and in the diagnosis of obstructive sleep apnea syndrome (OSAS) was evaluated in 50 subjects suspected for OSAS, simultaneously studied by polysomnography (PSG) in a sleep laboratory. Recordings were analysed by separate scorers, blinded to the results of the paired recording. The number of central (Ac), obstructive (Ao) or mixed apneas (Am), of hypopneas (H), and the total number of ventilatory disorders (AH) per hour of time in bed (TIB) calculated on the two recordings were significantly correlated. Bland and Altman analysis showed a good agreement between AH/TIB, Ac/TIB, Am/TIB and mean AH duration; a lower Ao/TIB at PM was mirrored by a higher H/TIB. Forty-two subjects had OSAS according to an apnea/hypopnea index (AHI) > or = 10 at PSG. Due to low sleep efficiency, AH/TIB was substantially lower than AHI. However an AH/TIB > or = 5 at PM showed a sensitivity of 100% and a specificity of 71.4%, while an AH/TIB > or = 10 showed a sensitivity of 95.2% and a specificity of 100%. In conclusion, PM proved reliable for recognition of the characteristics of ventilatory disorders and for diagnosis of OSAS.

Influence of sampling interval on the evaluation of nocturnal blood pressure in subjects with and without obstructive sleep apnoea.

Blood pressure (BP) variability during sleep is high in obstructive sleep apnoea syndrome (OSAS). How BP sampling interval affects the estimate of mean nocturnal BP in OSAS and control subjects was investigated. Nine subjects with apnoea/hypopnoea index (AHI) <5 and 18 OSAS patients with AHI >30 underwent nocturnal polysomnography with beat-by-beat BP monitoring. Mean nocturnal BP was evaluated averaging: a) all systolic (Ps) and diastolic (Pd) BP values; b) Ps and Pd sampled every 5, 10, 15, 20, and 30 min. The sampling starting point was repeatedly shifted, and several mean BP estimates for each sampling interval were obtained. Differences (deltaPs and deltaPd) between means obtained by sampling BP and by averaging all BP values were calculated. In both groups deltaPs and deltaPd scatter increased as sampling interval increased; their variance was always higher in OSAS subjects (p<0.001). Over 95% of deltaPs and deltaPd were <5% of the beat-by-beat mean values at all sampling intervals in controls, but this occurred only at sampling intervals < or =10 min in OSAS subjects. To conclude, for each blood pressure sampling time, a larger number of inaccurate nocturnal mean blood pressure estimates are obtained in obstructive sleep apnoea syndrome than in control subjects. Obstructive sleep apnoea syndrome subjects require more frequent blood pressure measurements to obtain a similar accuracy in nocturnal blood pressure evaluation.

Endogenous digitalislike factors in obstructive sleep apnea.

Recent studies have provided evidence that hypoxia may stimulate the release of endogenous digitalislike factors (EDLF). Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia during sleep and may be associated with sympathetic activation and a high risk of developing hypertension. This study was designed to measure EDLF in the plasma of patients with OSA diagnosed by polysomnography, with patients being classified by the number of apneic-hypopneic episodes/h sleep (apnea-hypopnea index, AHI). Plasma was obtained in the morning from 8 male normotensive OSA patients (OSA-N) (AHI 70+/-6), 2 untreated hypertensive OSA patients (OSA-HT), and 11 age-matched healthy male controls (C). EDLFs of different hydrophobicities were separated from the same plasma sample by solid-state C18-cartridges with 25% acetonitrile (ACN) (EDLF-1) followed by 40% ACN (EDLF-2). This procedure recovered ouabain in the first fraction and digoxin and digoxigenin in the second. EDLF was quantified in pM ouabain-equivalents by a human placenta radioreceptor assay. EDLF-1 levels were similar for OSA-N and C (231+/-55 vs. 258+/-58), whereas EDLF-2 levels were increased in OSA-N (244+/-51 vs. 110+/-25 in C, p=0.02). Norepinephrine was increased in apneics. The two OSA-HT had EDLF and norepinephrine levels similar to OSA-N. These preliminary results suggest that OSA is associated with an increase in the more hydrophobic EDLF levels in both normotensive and hypertensive states. No significant increase was found for the less hydrophobic ouabain-like EDLF.

Blood pressure and heart rate during periodic breathing while asleep at high altitude.

The ventilatory and arterial blood pressure (ABP) responses to isocapnic hypoxia during wakefulness progressively increased in normal subjects staying 4 wk at 5,050 m (Insalaco G, Romano S, Salvaggio A, Braghiroli A, Lanfranchi P, Patruno V, Donner CF, and Bonsignore G; J Appl Physiol 80: 1724-1730, 1996). In the same subjects (n = 5, age 28-34 yr) and expedition, nocturnal polysomnography with ABP and heart rate (HR) recordings were obtained during the 1st and 4th week to study the cardiovascular effects of phasic (i.e., periodic breathing-dependent) vs. tonic (i. e., acclimatization-dependent) hypoxia during sleep. Both ABP and HR fluctuated during non-rapid eye movement sleep periodic breathing. None of the subjects exhibited an ABP increase during the ventilatory phases that correlated with the lowest arterial oxygen saturation of the preceding pauses. Despite attenuation of hypoxemia, ABP and HR behaviors during sleep in the 4th wk were similar to those in the 1st wk. Because ABP during periodic breathing in the ventilatory phase increased similarly to the ABP response to progressive hypoxia during wakefulness, ABP variations during ventilatory phases may reflect ABP responsiveness to peripheral chemoreflex sensitivity rather than the absolute value of hypoxemia, suggesting a major tonic effect of hypoxia on cardiorespiratory control at high altitude.

Myocardial ischemia during sleep.

The role of sleep in the pathogenesis of coronary ischaemic events such as myocardial infarction, transient myocardial ischaemia, or cardiac sudden death, is unclear. This review will analyse the available data on the subject according to: (i) the autonomic and cardiovascular changes during sleep that may potentially favour myocardial ischaemia; (ii) the evidence of a circadian distribution of coronary events; and (iii) the factors possibly involved in the pathogenesis of nocturnal angina. Available data suggest that myocardial ischaemia may occur by different mechanisms in non-rapid eye movement (NREM) (decreased coronary perfusion pressure) and rapid eye movement (REM) sleep (increased myocardial oxygen demand). Coronary events show a major peak of occurrence between 6.00 a.m. and noon; however, the myocardial ischaemic threshold, defined as the heart rate value at which myocardial ischaemia develops, may be lower at night than during the daytime, suggesting an unexpectedly higher susceptibility to myocardial ischaemia during sleep than during wakefulness. These data warrant further study on the pathophysiology of coronary circulation during sleep. Finally, some evidence is available that sleep disordered breathing may precipitate nocturnal angina especially in REM sleep, through decreased arterial oxygen content secondary to hypoventilation or true apnoeas. More data are needed to better understand the effects of sleep on the coronary circulation, and to improve the therapeutic approach of nocturnal angina.

Effects of high-altitude periodic breathing on sleep and arterial oxyhaemoglobin saturation.

This study aimed to investigate the effect of periodic breathing (PB) at high altitude on sleep structure and arterial oxygen saturation (Sa,O2). Five healthy subjects underwent polysomnographic studies at sea level, and during the first and the fourth week of sojourn at 5,050 m. Their breathing pattern, sleep architecture and Sa,O2 were analysed. PB was detected in the high-altitude studies during nonrapid eye movement (NREM) sleep and tended to increase from the first to the fourth week. Stages 3-4 were absent in four subjects at the first week, but only in one at the fourth week, irrespective of the amount of PB. The arousal index was 11.6+/-3.8 at sea level, 30.1+/-15.5 at the first week at altitude and 33.0+/-18.2 at the fourth week. At altitude, arousal index in NREM sleep was higher during PB than during regular breathing. In NREM sleep, the mean highest Sa,O2 levels in NREM epochs with PB were higher than in those with regular breathing by 2.8+/-1.7% at the first week and 2.9+/-1.5% at the fourth week (p<0.025). From the first to the fourth week, mean Sa,O2 increased significantly during wakefulness (5.6%), NREM (5.2% with regular breathing and 5.3% with PB) and rapid eye movement sleep (7.6%). The data demonstrate a slight role of periodic breathing in altering sleep architecture at high altitude and also show that periodic breathing induces only a minor improvement in arterial oxygen saturation during nonrapid eye movement sleep.

Gender and the systemic hypertension-snoring association: a questionnaire-based case-control study.

Since the role of gender in the association between hypertension and snoring is unknown, we studied it while accounting for age and body mass index (BMI) as confounding variables. A questionnaire on snoring was administered to 90 hypertensive (HT) subjects (45 men and 45 women) and to 90 normotensive (NT) subjects matched for gender, age and BMI. As expected, snoring was more commonly reported by men than by women, but no significant difference was found between HT and NT men, irrespective of age. Conversely, heavy snoring was more frequently reported by HT than NT women; habitual snoring was more common among young (age < 50 years) HT than NT women; and heavy snoring was more common among older (age > 50 years) HT than NT women. These data suggest an effect of gender on the hypertension-snoring association: in men, snoring may be accounted for by age and BMI whether or not hypertension is present, whereas in women the natural history of snoring appears different and more severe in HT than in NT. Although the mechanism(s) responsible for the differences between men and women are obscure at present, gender may be an important variable in the systemic hypertension-snoring association.

What is the evidence that obstructive sleep apnoea is an important illness?

Obstructive sleep apnoea (OSA) is described by some authors as a potentially lethal disease and by others as an almost harmless condition. Excessive daytime sleepiness, neuropsychological dysfunction, altered quality of life, cardiovascular disease (systemic and pulmonary hypertension, cardiac arrhythmias, stroke and ischaemic heart disease) and increased mortality have been described as OSA complications. There is little argument that OSA may determine sleepiness, alter cognitive functions, and worsen quality of life, although with great interindividual variability: this should induce OSA to be considered an important illness per se, since sleepiness in OSA was shown to lead to important consequences, like road traffic accidents. Besides, OSA may interact with coexisting cardiac and respiratory disease and favour the appearance of heart and respiratory failure. Therefore, OSA is certainly also worth careful consideration as an important aggravating factor of other diseases. The evidence that obstructive sleep apnoea is an independent risk factor for cardiovascular complications other than owing to the recurrent transient blood pressure surges associated with apnoeas during sleep, and for an increased mortality is more conflicting. More studies are necessary to identify which characteristics of obstructive sleep apnoea may be considered important markers of its severity and as risk factors for different possible complications.