The inflammasome pathway in stable COPD and acute exacerbations.

Chronic obstructive pulmonary disease (COPD) is characterised by pulmonary and systemic inflammation that bursts during exacerbations of the disease (ECOPD). The NLRP3 inflammasome is a key regulatory molecule of the inflammatory response. Its role in COPD is unclear. We investigated the NLRP3 inflammasome status in: 1) lung tissue samples from 38 patients with stable COPD, 15 smokers with normal spirometry and 14 never-smokers; and 2) sputum and plasma samples from 56 ECOPD patients, of whom 41 could be reassessed at clinical recovery. We observed that: 1) in lung tissue samples of stable COPD patients, NLRP3 and interleukin (IL)-1ß mRNA were upregulated, but both caspase-1 and ASC were mostly in inactive form, and 2) during infectious ECOPD, caspase-1, oligomeric ASC and associated cytokines (IL-1ß, IL-18) were significantly increased in sputum compared with clinical recovery. The NLRP3 inflammasome is primed, but not activated, in the lungs of clinically stable COPD patients. Inflammasome activation occurs during infectious ECOPD. The results of this study suggest that the inflammasome participates in the inflammatory burst of infectious ECOPD.

Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial.

OBJECTIVE: To assess the effect of continuous positive airway pressure (CPAP) on 24 hour ambulatory blood pressure monitoring values in a large number of patients with untreated systemic hypertension of new onset and obstructive sleep apnoea. DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: Eleven general hospitals in Spain between 2004 and 2007. PARTICIPANTS: 340 patients recently diagnosed as having systemic hypertension by a general practitioner (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or both) and an apnoea-hypopnoea index per hour of sleep of >15 events/hour. INTERVENTION: Patients were assigned to CPAP (n=169) or sham CPAP (n=171) for three months. Main outcome measurements Net changes in the different 24 hour ambulatory blood pressure monitoring values from baseline to three months of optimal or sham CPAP. RESULTS: 277 (81%) of the 340 patients randomised were men; the patients had a mean age of 52.4 (SD 10.5) years, a body mass index of 31.9 (5.7), an Epworth sleepiness scale score of 10.1 (4.3), an apnoea-hypopnoea index of 43.5 (24.5). No differences between groups were seen at baseline. Compared with placebo and analysed by intention to treat, the mean 24 hour ambulatory blood pressure of the CPAP group decreased by 1.5 (95% confidence interval: 0.4 to 2.7) mm Hg (P=0.01). The mean 24 hour ambulatory blood pressure monitoring measures decreased by 2.1 mm Hg (0.4 to 3.7) mm Hg (P=0.01) for systolic pressure and 1.3 (0.2 to 2.3) mm Hg (P=0.02) for diastolic blood pressure. Mean nocturnal blood pressure decreased by 2.1 (0.5 to 3.6) mm Hg (P=0.01). CONCLUSIONS: CPAP produced a statistically significant reduction in blood pressure in patients with systemic hypertension and obstructive sleep apnoea. This reduction is small and did not achieve the 3 mm Hg drop in mean 24 hour ambulatory blood pressure that the trial was powered to detect. Consequently, these results may have uncertain clinical relevance. However, taking into account the prevalence of hypertension and the likelihood of comorbidities, the decrease in blood pressure, although minimal, may be beneficial. TRIAL REGISTRATION: Clinical trials NCT00202527.

Changes in management of chronic obstructive pulmonary disease (COPD) in primary care: EMMEPOC study.

BACKGROUND: Changes in management of COPD in primary care were studied following a training exercise among Spanish general practitioners (GPs). The exercise involved dissemination of the Spanish Society for Pulmonology and Thoracic Surgery (SEPAR) guidelines. The use of a portable device to perform spirometry tests was evaluated to adequately categorize COPD and reduce other diagnostic interventions. METHODS: A representative sample of GPs from general practices in Spain was recruited for the study. In phase I, GPs performed an initial evaluation of 5 patients with COPD. In phase II, GPs were randomly allocated to the following groups: 1) control group-G1 (GPs managing COPD according to usual clinical practice); 2) training group-G2 (dissemination of SEPAR guidelines); and 3) training group-G3 (dissemination of SEPAR guidelines and distribution of the Koko Peak Pro to measure FEV(1), FEV(6), and FEV(1)/FEV(6)). RESULTS: Phase-I included 3254 physicians, who selected 16,024 patients. In phase II, 301 physicians in G1, 1182 in G2, and 1141 in G3 selected 1481, 5798, and 5556 patients respectively. Evaluation of the changes in COPD stratification according to the SEPAR guidelines showed that physicians in G1 adequately classified 60% of patients, compared to 69% in G2 and 88.5% in G3 (p<0.0001). On comparing groups G1 and G3, a significant reduction was seen in chest X-rays (from 42% to 32%, p=0.0002) and arterial blood gas studies performed (from 34% to 22%, p<0.0001). CONCLUSIONS: The dissemination of the SEPAR guidelines and the utilization of the portable device for spirometry may improve management of COPD in primary care.

Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study.

BACKGROUND AND PURPOSE: Continuous positive airway pressure (CPAP) is an effective treatment for sleep apnea (SA), although the evidence for improving chronic heart failure (CHF) is inconclusive. Our aim was to evaluate the effect of CPAP treatment on the left ventricle ejection fraction (LVEF) among other cardiological variables in a randomized, multicenter, placebo (sham-CPAP)-controlled study. METHODS: After the selection procedure, 60 patients with CHF with LVEF<45% and SA with an apnea-hypopnea index (AHI)>10/h were evaluated at baseline, and after 3 months of treatment with optimal CPAP or sham-CPAP. The assessment was based on the LVEF, hypertension, daytime sleepiness (Epworth sleepiness scale [ESS]), quality of life (SF-36), New York Heart Scale (NYHA score), dyspnea (by using the Borg scale) and exercise tolerance (6-min walk test). RESULTS: The mean AHI was normalized in the optimal CPAP group but not in the sham-CPAP group. The LVEF showed a significant improvement in the group of patients treated with CPAP (2.5; 95% CI: 0.6 to 4.3), which was not observed in the sham-CPAP group (0.0; 95% CI: -2.1 to 2.1). However, the change in the LVEF from baseline to 3 months was not significantly greater in the whole group (obstructive and Cheyne-Stokes events) treated with CPAP than in the control group (p: 0.07). In patients with only obstructive sleep apnea (OSA), who account for 83% of the total population, there was a significant improvement in the LVEF in the group of patients treated with CPAP but no such improvement in the sham-CPAP group. In this OSA group, the change in the LVEF from baseline to 3 months was significantly greater in the group treated with CPAP than in the sham-CPAP group (p: 0.03). The other variables studied were not modified. When the patients were divided according to the severity of the LVEF (a LVEF cut-off of 30%), improvement was observed in those with a LVEF>30. No changes were found in the other cardiological variables. CONCLUSIONS: CPAP therapy proved to be useful in patients with associated sleep-disordered breathing and CHF. The improvement was more marked in patients with a LVEF>30%. However, the increased LVEF in the CPAP group was not accompanied by changes in the other cardiological variables.

Management of sleep apnea: concordance between nonreference and reference centers.

BACKGROUND: When a disorder is as prevalent as sleep apnea-hypopnea syndrome (SAHS), different medical levels and approaches should be involved in facilitating the diagnosis, at least, of patients with symptoms that disrupt social or working life, and of risk groups such as professional drivers. We sought to analyze the degree of concordance between management and treatment decisions for SAHS patients at sleep reference centers (RCs) and at non-RCs (NRCs). MATERIALS AND METHODS: Eighty-eight consecutive patients with suspected SAHS were referred by family doctors to the NRC. The patients were studied randomly at the RC, using full polysomnography, and at the NRC, employing respiratory polygraphy. The concordance in the therapeutic approach between both centers was analyzed via the outcomes, and the physiologic variables of the sleep studies were also evaluated. RESULTS: The concordance in the final clinical decision was substantial. There was a good agreement with respect to apnea-hypopnea index as a categoric variable and as a continuous variable. CONCLUSIONS: These results suggest that respiratory physicians with simple sleep studies are able to manage a large number of patients with SAHS. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT 00424658.

Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome.

Flow limitation during sleep occurs when the rise in esophageal pressure is not accompanied by a flow increase which results in a non-rounded inspiratory flow shape. Short periods of flow limitation ending in an arousal or in a fall in SaO2 (hypopnea or upper airway resistance syndrome) are detrimental but the role of prolonged periods of flow limitation (PPFL) has not yet been clarified. This is important not only for diagnosis but also for nasal continuous positive airway pressure (CPAP) titration, especially for the automatic devices that need to be setup. The aim of this study was to analyze the effects of PPFL. We compared the behavior of the mean end-expiratory systemic blood pressure (SBP), end-tidal CO2, esophageal pressure and the pattern of breathing during a period of normal breathing at optimal (CPAP) and during PPFL at suboptimal CPAP in 14 patients with sleep apnea/hypopnea syndrome during a full polysomnography CPAP titration. The mean values of the parameters studied, at optimal and suboptimal CPAP were (1) SBP 92+/-13 vs. 91+/-15 mmHg (P: ns). At suboptimal CPAP, swings of blood pressure were associated with changes in pleural pressure; (2) SaO2 97.5+/-1.2 vs. 96.5+/-1.6 (P: 0.03), (3) end-tidal CO2 43.5+/-4 vs. 49.5+/-4 (P:0.001); (4) oesophageal pressure, 10.5+/-4 vs. 37.6+/-15 cmH2O (P:0.001) and (5) pattern of breathing: minute ventilation 6.6+/-1.4 vs. 6.1+/-1.2L/min (P: ns) and inspiratory time 1.24+/-0.3 vs. 1.66+/-0.4s (P:0.001). It can be concluded that PPFL induces significant physiological changes. Nevertheless, given the scant literature, clinical studies are warranted to elucidate the clinical role of these physiological changes.

Effect of using the flow or the volume signals on the measurement of nonapneic respiratory events.

STUDY OBJECTIVES: To assess whether the measurement of breathing reduction during obstructive sleep events depends on using the flow or the volume signals recorded with a pneumotachograph. DESIGN: Prospective observational study. SETTING: Sleep laboratory in a University Hospital. PATIENTS OR PARTICIPANTS: Data from 10 male patients with sleep apnea (54 +/- 11 years, apnea-hypopnea index: 43 +/- 21 events/hour, body mass index: 30 +/- 2 kg/m2). INTERVENTIONS: Slow modification of continuous positive airway pressure was performed during full-polysomnography continuous positive airway pressure titration. MEASUREMENTS AND RESULTS: Air flow was measured by a pneumotachograph, and volume was computed by numerical integration. Obstructive events of different magnitude were selected. In 500 breathing cycles analyzed, the reduction in tidal volume was greater than the reduction in the flow amplitude: mean difference of 0.091 (i.e., 9.1% amplitude) and limits of agreement of 0.095 and -0.277 (i.e., 9.5% and -27.7% amplitude). In 14% of the cycles, the reduction in flow was < 50%, whereas the reduction in volume was > 50%, resulting in discordant event classification. CONCLUSIONS: The quantification of breathing reduction depends on whether the flow or the volume signal is used to assess breathing during sleep.

Static and dynamic upper airway obstruction in sleep apnea: role of the breathing gas properties.

Increased upper airway collapsibility in the sleep apnea/hypopnea syndrome (SAHS) is usually interpreted by a collapsible resistor model characterized by a critical pressure (Pcrit) and an upstream resistance (Rup). To investigate the role played by the upstream segment of the upper airway, we tested the hypothesis that breathing different gases would modify Rup but not Pcrit. The study was performed on 10 patients with severe SAHS (apnea-hypopnea index: 59 +/- 14 events/hour) when breathing air and helium-oxygen (He-O2) during non-REM sleep. The continuous positive airway pressure that normalized flow (CPAPopt) was measured. Rup and Pcrit were determined from the linear relationship between maximal inspiratory flow VImax and nasal pressure (PN):VImax = (PN - Pcrit)/Rup. Changing the breathing gas selectively modified the severity of dynamic (CPAPopt, Rup) and static (Pcrit) obstructions. CPAPopt was significantly (p = 0.0013) lower when breathing He-O2 (8.44 +/- 1.66 cm H2O; mean +/- SD) than air (10.18 +/- 2.34 cm H2O). Rup was markedly lower (p = 0.0001) when breathing He-O2 (9.21 +/- 3.93 cm H2O x s/L) than air (15.92 +/- 6.27 cm H2O x s/L). Pcrit was similar (p = 0.039) when breathing He-O2 (4.89 +/- 2.37 cm H2O) and air (4.19 +/- 2.93 cm H2O). The data demonstrate the role played by the upstream segment of the upper airway and suggest that different mechanisms determine static (Pcrit) and dynamic (Rup) upper airway obstructions in SAHS.

[Results of a preventive program and assisted hospital discharge for COPD exacerbation. A feasibility study]. / Resultados de dos programas con intervención domiciliaria dirigidos a pacientes con enfermedad pulmonar obstructiva crónica evolucionada.

BACKGROUND AND OBJECTIVE: Exacerbation of chronic obstructive pulmonary disease (COPD) is one of the most frequent causes of hospital admission. We examined the results and feasibility of two programs conducted by a hospital respiratory unit aimed to reduce both the length of hospital stay and the number of hospital admissions for COPD acute exacerbation. PATIENTS AND METHOD: a) Assisted hospital discharge program: Patients admitted for acute exacerbation who met our criteria for early discharge were sent home with the support of a respiratory nurse. Home visits were carried out and direct phone contact with the nurse and physician was provided during a limited period of 6 weeks. Outcome variables studied were length of hospital admission and need for hospital reentry. b) Exacerbation prevention program: A group of patients with severe COPD and at least 3 hospital admissions for exacerbation during the previous year were included. These patients underwent an educational program and were given unlimited direct phone access to the respiratory nurse and physician. When necessary, home visits were carried out. The main outcome variable of this program was the number of hospital admissions. RESULTS: a) Assisted hospital discharge program: A total of 97 patients were included. The mean length of hospital stay was 5.4 1.7 days, which was significantly shorter than the previous average length of stay in our respiratory unit for a diagnosis of COPD exacerbation (8.52 days). The rate of hospital reentry was 17% (within the first 3 months). b) Exacerbation prevention program: 23 patients were enrolled. In this group, the number of hospital admissions decreased significantly from 5.0 1.8 to 1.7 2.4 per year (p = 0.001). Visits to the emergency department were also decreased, from 1.2 1.6 to 0.4 1.6 per patient (p = 0.05). Finally, the length of hospital stay decreased from 38 17 to 16 20 days (p = 0.0001). CONCLUSIONS: A combined use of hospital resources and home care programs which are specifically addressed to severe COPD patients can reduce the need for hospital admission.

Resultados de dos programas con intervención domiciliaria dirigidos a pacientes con enfermedad pulmonar obstructiva crónica evolucionada / Results of a preventive program and assisted hospital discharge for COPD exacerbation. A feasibility study

FUNDAMENTO Y OBJETIVO: Se estudiaron la viabilidad y los resultados de dos programas dirigidos a la reducción tanto de la estancia media por paciente como del número de ingresos en pacientes con enfermedad pulmonar obstructiva crónica (EPOC). PACIENTES Y MÉTODO: Según el programa de alta temprana, los pacientes ingresados por agudización que cumplían los criterios definidos de alta temprana fueron remitidos a su domicilio y controlados por personal de enfermería del servicio de neumología. Se realizaron visitas domiciliarias y se procuró el contacto telefónico directo con los equipos de enfermería y médico durante 6 semanas. En el programa de prevención de agudizaciones se incluyó a pacientes con EPOC evolucionada y un mínimo de tres ingresos hospitalarios durante el año precedente. Estos pacientes siguieron un programa formativo y disponían de acceso telefónico directo ilimitado con el equipo, además del control mediante visitas domiciliarias. RESULTADOS: En el programa de alta temprana se incluyó a 97 pacientes. La estancia media (DE) hospitalaria fue de 5,4 (1,7) días, significativamente inferior a la estancia media previamente registrada para pacientes con EPOC agudizada (8,52 días el año previo al inicio del programa). La proporción de reingresos hospitalarios tempranos (primeros 3 meses) fue del 17 por ciento. En el programa de prevención de agudizaciones se incluyó a 23 pacientes. Los ingresos hospitalarios disminuyeron de 5,0 (1,8) a 1,7 (2,4) por año (p = 0,001). Las consultas al servicio de urgencias sin hospitalización disminuyeron de 1,2 (1,6) a 0,4 (1,6) por paciente (p = 0,05).Finalmente, la estancia media hospitalaria descendió de 38 (17) a 16 (20) días (p = 0,0001). CONCLUSIONES: Una combinación de utilización de recursos hospitalarios y programas sencillos de atención domiciliaria puede reducir la estancia media y el número de ingresos hospitalarios de pacientes con EPOC (AU)

Potential rebreathing after continuous positive airway pressure failure during sleep.

BACKGROUND: Continuous positive airway pressure (CPAP) is widely applied as a home treatment during sleep. Conventional CPAP devices are based on a blower to generate nasal pressure and to maintain air washout from the circuit. Because common CPAP systems do not incorporate alarms, failure in the device or in the electric supply could result in rebreathing. AIM: To assess the potential rebreathing to which a patient could be subjected after CPAP failure. METHODS: Four conventional CPAP devices, PV100 (Breas Medica; Molnlycke, Sweden), CP90 (Taema; Antony, France), and SoloPlus and BiPAP (Respironics, Murrysville, PA), and three common exhalation ports (Whisper Swivel [Respironics], Plateau [Respironics], and 4-mm orifice) were tested in a bench study. Rebreathing after failure was assessed by measuring the resistance of the exhalation port (REP) and the resistance of the tubing plus CPAP device (RTUB), and by measuring O(2) and CO(2) concentrations in the nasal mask in a subject breathing through a CPAP system. RESULTS: REP was much higher (approximately 30 cm H(2)O x s/L) than RTUB (approximately 1 cm H(2)O x s/L). Most (approximately 90%) of the breathing tidal volume would flow from/to the tubing plus CPAP device, which represents a dead space (> or = 0.5 L) similar to the patient's tidal volume. After CPAP failure, end-tidal O(2) in the mask changed from 16.8 to 9.2% and end-tidal CO(2) in the mask changed from 4.2 to 6.2%. By contrast, O(2) and CO(2) did not change when a nonrebreathing valve was placed in the mask. CONCLUSIONS: Common CPAP systems run a risk of inducing rebreathing in case of failure. This risk could be easily avoided by including a passive valve in the apparatus.