Small particle-size talc is associated with poor outcome and increased inflammation in thoracoscopic pleurodesis

Rationale: Talc is very effective for pleurodesis, but there is concern about complications, especially acute respiratory distress syndrome. Objectives: It was the aim of this study to investigate if talc with a high concentration of small particles induces greater production of cytokines, and if pleural tumor burden has any influence on the local production and spillover of cytokines to the systemic circulation and eventual complications. Methods: We investigated 227 consecutive patients with malignant effusion submitted to talc pleurodesis. One hundred and three patients received 'small-particle talc' (ST; containing about 50% particles <10 ¿m) and 124 received 'large-particle talc' (with <20% particles <10 ¿m). Serial samples of both pleural fluid and blood were taken before and 3, 24, 48 and 72 h after thoracoscopy. Also, mesothelial cells were stimulated with both types of talc in vitro. Measurements and Results: Interleukin-8, tumor necrosis factor-¿, vascular endothelial growth factor, basic fibroblast growth factor and thrombin-antithrombin complex were measured in all samples. Early death (<7 days after talc) occurred in 8 of 103 patients in the ST and in 1 of 124 in the 'large-particle talc' group (p = 0.007). Patients who received ST had significantly higher proinflammatory cytokines in pleural fluid and serum after talc application, and also in supernatants of the in vitro study. Pleural tumor burden correlated positively with proinflammatory cytokines in serum, suggesting that advanced tumor states induce stronger systemic reactions after talc application. Conclusions: ST provokes a strong inflammatory reaction in both pleural space and serum, which is associated with a higher rate of early deaths observed in patients receiving it.Instituto de Salud Carlos III FIS 04/028

Small particle-size talc is associated with poor outcome and increased inflammation in thoracoscopic pleurodesis

Rationale: Talc is very effective for pleurodesis, but there is concern about complications, especially acute respiratory distress syndrome. Objectives: It was the aim of this study to investigate if talc with a high concentration of small particles induces greater production of cytokines, and if pleural tumor burden has any influence on the local production and spillover of cytokines to the systemic circulation and eventual complications. Methods: We investigated 227 consecutive patients with malignant effusion submitted to talc pleurodesis. One hundred and three patients received 'small-particle talc' (ST; containing about 50% particles <10 ¿m) and 124 received 'large-particle talc' (with <20% particles <10 ¿m). Serial samples of both pleural fluid and blood were taken before and 3, 24, 48 and 72 h after thoracoscopy. Also, mesothelial cells were stimulated with both types of talc in vitro. Measurements and Results: Interleukin-8, tumor necrosis factor-¿, vascular endothelial growth factor, basic fibroblast growth factor and thrombin-antithrombin complex were measured in all samples. Early death (<7 days after talc) occurred in 8 of 103 patients in the ST and in 1 of 124 in the 'large-particle talc' group (p = 0.007). Patients who received ST had significantly higher proinflammatory cytokines in pleural fluid and serum after talc application, and also in supernatants of the in vitro study. Pleural tumor burden correlated positively with proinflammatory cytokines in serum, suggesting that advanced tumor states induce stronger systemic reactions after talc application. Conclusions: ST provokes a strong inflammatory reaction in both pleural space and serum, which is associated with a higher rate of early deaths observed in patients receiving it. Copyright © 2012 S. Karger AG, Basel.Peer Reviewe

Echocardiographic Changes with Positive Airway Pressure Therapy in Obesity Hypoventilation Syndrome. Long-Term Pickwick Randomized Controlled Clinical Trial

Spanish Sleep Network.[Rationale] Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking. Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking.[Objectives] In a prespecified secondary analysis of the largest multicenter randomized controlled trial of OHS (Pickwick Project; N = 221 patients with OHS and coexistent severe obstructive sleep apnea), we compared the effectiveness of three years of NIV and CPAP on structural and functional echocardiographic changes.[Methods] At baseline and annually during three sequential years, patients underwent transthoracic two-dimensional and Doppler echocardiography. Echocardiographers at each site were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group and repeated measures interaction to determine the differential effect between CPAP and NIV. Measurements and Main Results: A total of 196 patients were analyzed: 102 were treated with CPAP and 94 were treated with NIV. Systolic pulmonary artery pressure decreased from 40.5 ± 1.47 mm Hg at baseline to 35.3 ± 1.33 mm Hg at three years with CPAP, and from 41.5 ± 1.56 mm Hg to 35.5 ± 1.42 with NIV (P < 0.0001 for longitudinal intragroup changes for both treatment arms). However, there were no significant differences between groups. NIV and CPAP therapies similarly improved left ventricular diastolic dysfunction and reduced left atrial diameter. Both NIV and CPAP improved respiratory function and dyspnea.[Conclusions] In patients with OHS who have concomitant severe obstructive sleep apnea, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and left ventricular diastolic dysfunction

Evaluation of the Diagnostic Accuracy of Non-Specific Bronchial Provocation Tests in the Diagnosis of Asthma: A Randomized Cross-Over Study

[Introduction] The role of bronchial provocation tests in the diagnosis of asthma remains to be fully explored. We aimed to evaluate methacholine and mannitol challenge testing, and explore the factors associated with this broncoprovocation response.[Methods] Observational, cross-over, randomized trial evaluating adult cases with suspected asthma, naïve to treatment, with normal pre-bronchodilator spirometry, and negative bronchodilator test. Patients were randomized to start with methacholine or mannitol. The diagnosis of bronchial asthma was confirmed if there was a good functional and clinical response to one month with twice daily formoterol/budesonide 9/320. The diagnostic profile and the concordance were calculated. Factors associated with a positive provocation test were entered into a multivariate binomial logistic regression analysis, and classification trees were created for both tests.[Results] The study included 108 cases (50.0% diagnosed with asthma and 51.9% cases starting with methacholine). The percentage of cases positive to methacholine and mannitol were 30.6% and 25.0% respectively. Kappa values were 0.40 (p 26 ppb, FEV1 ≤ 103.3% and female sex correctly classified 78.7% of methacholine responders. FENO value > 26 ppb was enough to correctly classify 81.5% of mannitol responders.[Conclusions] Our study confirms the diagnostic profile of methacholine and mannitol challenge tests and describes the variable associated to their positivity with new proposed cutoff values.This project has been funded by a research grant from the Neumosur Foundation (project no. 01.2009).Peer reviewe

El impacto de la terapia de presión positiva de larga duración en el síndrome de hipoventilación-obesidad en función de la gravedad de la enfermedad

[Rationale] Obesity hypoventilation syndrome (OHS) with concomitant severe obstructive sleep apnea (OSA) is treated with CPAP or noninvasive ventilation (NIV) during sleep. NIV is costlier, but may be advantageous because it provides ventilatory support. However, there are no long-term trials comparing these treatment modalities based on OHS severity.[Objective] To determine if CPAP have similar effectiveness when compared to NIV according to OHS severity subgroups.[Methods] Post hoc analysis of the Pickwick randomized clinical trial in which 215 ambulatory patients with untreated OHS and concomitant severe OSA, defined as apnoea-hypopnea index (AHI) ≥ 30 events/h, were allocated to NIV or CPAP. In the present analysis, the Pickwick cohort was divided in severity subgroups based on the degree of baseline daytime hypercapnia (PaCO2 of 45–49.9 or ≥50 mmHg). Repeated measures of PaCO2 and PaO2 during the subsequent 3 years were compared between CPAP and NIV in the two severity subgroups. Statistical analysis was performed using linear mixed-effects model.[Results] 204 patients, 97 in the NIV group and 107 in the CPAP group were analyzed. The longitudinal improvements of PaCO2 and PaO2 were similar between CPAP and NIV based on the PaCO2 severity subgroups.[Conclusion] In ambulatory patients with OHS and concomitant severe OSA who were treated with NIV or CPAP, long-term NIV therapy was similar to CPAP in improving awake hypercapnia, regardless of the severity of baseline hypercapnia. Therefore, in this patient population, the decision to prescribe CPAP or NIV cannot be solely based on the presenting level of PaCO2.[Introducción] El síndrome de hipoventilación-obesidad (SHO) con apnea obstructiva del sueño (AOS) grave concomitante se trata con CPAPo ventilación no invasiva (VNI) durante el sueño. La VNI es más costosa, pero puede ser beneficiosa porque proporciona soporte ventilatorio; sin embargo, no existen estudios a largo plazo que comparen estas modalidades de tratamiento basándose en la gravedad del SHO.[Objetivo] Determinar si la CPAP tiene una eficacia similar a la VNI según los subgrupos de gravedad del SHO.[Métodos] Análisis a posteriori del ensayo clínico aleatorizado Pickwick en el que 215 pacientes ambulatorios con SHO sin tratar y con AOS grave concomitante (definida como un índice de apnea-hipopnea [IAH] ≥ 30 episodios/hora) recibieron tratamiento con VNI o CPAP. En el presente análisis, la cohorte Pickwick se dividió en subgrupos según la gravedad basándose en el grado de hipercapnia diurna al inicio del estudio (PaCO2 de 45-49.9 mm Hg o ≥ 50 mm Hg). Se compararon las mediciones periódicas de PaCO2 y PaO2 durante los 3 años siguientes entre la CPAP y la VNI entre los dos subgrupos de gravedad. Se realizó un análisis estadístico utilizando un modelo lineal mixto.[Resultados] Se analizaron 204 pacientes, 97 en el grupo de VNI y 107 en el grupo de CPAP. Las mejoras lineales de PaCO2 y PaO2 fueron similares entre la CPAP y la NIV según los subgrupos de gravedad en función de la PaCO2.[Conclusión] En los pacientes ambulatorios con SHO y AOS grave concomitante a los que se trató con VNI o CPAP, el tratamiento a largo plazo con VNI resultó similar a la CPAP, en cuanto a la mejora de la hipercapnia en vigilia, independientemente de la gravedad de la hipercapnia de inicio. Por lo tanto, en esta población de pacientes la decisión de prescribir CPAP o VNI no puede basarse exclusivamente en el nivel de partida de PaCO2.Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo, Madrid, Spain) PI050402, Spanish Respiratory Foundation 2005 (FEPAR) and Air Liquide Spain.Peer reviewe

Long-term clinical effectiveness of continuous positive airway pressure therapy versus non-invasive ventilation therapy in patients with obesity hypoventilation syndrome: a multicentre, open-label, randomised controlled trial

Spanish Sleep Network: Galo Fernández, Estrella Ordax-Carbajo, Nicolás González-Mangado, Teresa Gómez-García, María-Ángeles Martínez-Martínez, Elena Ojeda-Castillejo, Daniel López Padilla, Santiago J Carrizo, Begoña Gallego, Mercedes Pallero, Odile Romero, María Antonia Ramón, Eva Arias, Jesús Muñoz-Méndez, Cristina Senent, José N.Sancho-Chust, Nieves Belén Navarro Soriano, Emilia Barrot, José M. Benítez, Jesús Sánchez-Gómez, Rafael Golpe, Ana Santiago-Recuerda Silvia Gómez, Mónica Bengoa.[Background] Obesity hypoventilation syndrome is commonly treated with continuous positive airway pressure or non-invasive ventilation during sleep. Non-invasive ventilation is more complex and costly than continuous positive airway pressure but might be advantageous because it provides ventilatory support. To date there have been no long-term trials comparing these treatment modalities. We therefore aimed to determine the long-term comparative effectiveness of both treatment modalities.[Methods] We did a multicentre, open-label, randomised controlled trial at 16 clinical sites in Spain. We included patients aged 15–80 years with untreated obesity hypoventilation syndrome and an apnoea-hypopnoea index of 30 or more events per h. We randomly assigned patients, using simple randomisation through an electronic database, to receive treatment with either non-invasive ventilation or continuous positive airway pressure. Both investigators and patients were aware of the treatment allocation. The research team was not involved in deciding hospital treatment, duration of treatment in the hospital, and adjustment of medications, as well as adjudicating cardiovascular events or cause of mortality. Treating clinicians from the routine care team were not aware of the treatment allocation. The primary outcome was the number of hospitalisation days per year. The analysis was done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01405976.[Findings] From May 4, 2009, to March 25, 2013, 100 patients were randomly assigned to the non-invasive ventilation group and 115 to the continuous positive airway pressure group, of which 97 patients in the non-invasive ventilation group and 107 in the continuous positive airway pressure group were included in the analysis. The median follow-up was 5·44 years (IQR 4·45–6·37) for all patients, 5·37 years (4·36–6·32) in the continuous positive airway pressure group, and 5·55 years (4·53–6·50) in the non-invasive ventilation group. The mean hospitalisation days per patient-year were 1·63 (SD 3·74) in the continuous positive airway pressure group and 1·44 (3·07) in the non-invasive ventilation group (adjusted rate ratio 0·78, 95% CI 0·34–1·77; p=0·561). Adverse events were similar between both groups.[Interpretation] In stable patients with obesity hypoventilation syndrome and severe obstructive sleep apnoea, non-invasive ventilation and continuous positive airway pressure have similar long-term effectiveness. Given that continuous positive airway pressure has lower complexity and cost, continuous positive airway pressure might be the preferred first-line positive airway pressure treatment modality until more studies become available.This study was funded by the Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo; number PI050402), Spanish Respiratory Foundation 2005 (FEPAR), and Air Liquide Spain.Peer reviewe

Cost-effectiveness of positive airway pressure modalities in obesity hypoventilation syndrome with severe obstructive sleep apnoea

Background Obesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities. Objectives We performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure. Methods Hospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed. Results In total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91-3.14) years for NIV group and 3.00 (2.92-3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups. Conclusion CPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA. Trial registration number NCT01405976Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias, Ministerio de Sanidad y Consumo) PI050402, Spanish Respiratory Foundation 2005 (FEPAR) and Air Liquide Spain