Jean-Louis Racineux

Long-Term Outcome of Noninvasive Positive Pressure Ventilation for Obesity Hypoventilation Syndrome

BACKGROUND Few data are available on the long-term outcome of noninvasive positive pressure ventilation (NPPV) for obesity hypoventilation syndrome (OHS). This study was designed to determine long-term survival, treatment adherence, and prognostic factors in patients with OHS in whom NPPV was initiated in an acute setting vs under stable clinical conditions. METHODS One hundred thirty consecutive patients with OHS (56 women) who started NPPV between January 1995 and December 2006 either under stable conditions (stable group, n = 92) or during ICU management of acute hypercapnic exacerbation (acute group, n = 38) were retrospectively analyzed. RESULTS Arterial blood gases and the Epworth sleepiness scale were both significantly improved after 6 months of NPPV. With a mean follow-up of 4.1 +/- 2.9 years, 24 (18.5%) patients died and 24 (18.5%) discontinued NPPV. On Kaplan-Meier analysis, 1-, 2-, 3-, and 5-year survival probabilities were 97.5%, 93%, 88.3%, and 77.3%, respectively. Mortality was lower than that described in a previous series of patients with untreated OHS. Supplemental oxygen therapy was the only independent predictor of mortality. The probability of continuing NPPV was 80% at 3 years with a high rate of daily use ( > 7 h). Female sex was predictive of lower long-term adherence to NPPV. The acute and stable groups did not differ in terms of arterial blood gases and Epworth sleepiness scale at 6 months, long-term survival, and treatment adherence. CONCLUSIONS The results of this study support long-term NPPV as an effective and well-tolerated treatment of OHS whether initiated in the acute or chronic setting.

Microvascular endothelial function in obstructive sleep apnea: Impact of continuous positive airway pressure and mandibular advancement.

OBJECTIVES Endothelial dysfunction has been proposed as a potential mechanism implicated in the pathogenesis of cardiovascular complications of obstructive sleep apnea syndrome (OSAS). This study aimed to evaluate the microvascular endothelial function (MVEV) in OSAS and the impact on MVEF of 2 months of treatment with continuous positive airway pressure (CPAP) and mandibular advancement device (MAD). METHODS Microvascular reactivity was assessed using laser Doppler flowmetry combined with acetylcholine (Ach) and sodium nitroprusside (SNP) iontophoresis in 24 OSAS patients and 9 control patients. In 12 of the 24 OSAS patients, microvascular reactivity was reassessed after 2 months of CPAP and MAD using a randomized cross-over design. RESULTS Ach-induced vasodilation was significantly lower in OSAS patients than in matched controls and correlated negatively with apnea hypopnea index (r=-0.49, p<0.025) and nocturnal oxygen desaturations (r=-0.63, p<0.002). Ach-induced vasodilation increased significantly with both CPAP and MAD. The increase in Ach-induced vasodilation under OSAS treatment correlated with the decrease in nocturnal oxygen desaturations (r=0.48, p=0.016). CONCLUSION Our study shows an impairment of MVEF in OSAS related to OSAS severity. Both CPAP and MAD treatments were associated with an improvement in MVEF that could contribute to improve cardiovascular outcome in OSAS patients.

Lipid nanocapsules: Ready-to-use nanovectors for the aerosol delivery of paclitaxel

Aerosol drug delivery permits the development of dose-intensification strategies in severe, malignant lung diseases. The aim of the study was to demonstrate that the encapsulation of paclitaxel in lipid nanocapsules (LNCs), a novel drug nanocarrier for lipophilic components, allows one to provide pulmonary drug delivery of paclitaxel by nebulisation, thereby allowing preclinical and clinical studies. LNC dispersions are made into aerosols with commercial nebulisers. The structure, drug payload and cytotoxicity of nebulised LNCs were compared to fresh LNCs. The results demonstrated that LNC dispersions could be made into aerosols by using mesh nebulisers without altering the LNC structure. Only eFlow rapid-produced aerosols are compatible with human use: the mean duration to nebulise 3 ml of LNC dispersion is less than 9 min, with an aerosol mass median aerodynamic diameter equal to 2.7+/-0.1 microm and a fine-particle fraction (between 1.0 and 5.0 microm) of 81.5+/-3.1%. No modifications of drug payload or cytotoxicity effects of paclitaxel-loaded LNC (PTX-LNC) were observed. In order to carry out preclinical studies, a scaled-up LNC formulation protocol was used. Chemical parameters, such as acidity and osmolarity, were optimised, and a storage procedure for PTX-LNC batches was set-up. Animal studies are now needed to determine the tolerance and therapeutic potential of LNC dispersion aerosols.

Endothelial Dysfunction and Circulating Microparticles from Patients with Obstructive Sleep Apnea

Endothelial dysfunction is involved in vascular complications of obstructive sleep apnea (OSA). In this study, circulating microparticles (MPs) from patients with OSA-induced nocturnal desaturations were characterized and their effects on endothelial function were evaluated. Two age-matched groups of patients undergoing polysomnography for OSA were compared: 35 desaturators with a 3% oxyhemoglobin desaturation index (ODI) > or = 10 events per hour of sleep and 27 nondesaturators with ODI <10 events per hour. MPs were characterized by flow cytometry and then either used to treat in vitro human endothelial cells or to study endothelial function in mice. Circulating MPs did not differ between groups, but MPs from granulocytes and activated leukocytes (CD62L(+)) were found at higher levels in desaturators. In vitro, MPs from desaturators reduced endothelial nitric oxide (NO) production by enhancing phosphorylation of endothelial NO synthase at the site of inhibition and expression of caveolin-1. CD62L(+) MPs positively correlated with ODI. Endothelial NO production negatively correlated with both CD62L(+) MPs and ODI. MPs from desaturators increased expression of endothelial adhesion molecules including E-selectin, ICAM-1 and ITGA5, and cyclooxygenase 2. Moreover, injection of MPs from desaturators into mice impaired endothelium-dependent relaxation in aorta and flow-induced dilation in small mesenteric arteries. This study demonstrates an association between endothelial dysfunction and increased circulating levels of CD62L(+) MPs. This may initiate atherogenic processes in patients with OSA and severe nighttime hypoxia.

Mandibular Advancement for Obstructive Sleep Apnea: Dose Effect on Apnea, Long-Term Use and Tolerance

Background: Previous studies have documented an effect of mandibular advancement (MA) on pharyngeal airway size and collapsibility. Objectives: We aimed to describe the course of the apnea-hypopnea index (AHI) and the snoring index (SI) during progressive MA and to evaluate the long-term efficacy, tolerance and usage of MA therapy after progressive MA titration in sleep apnea patients. Methods: Sixty-six patients with obstructive sleep apnea syndrome underwent sequential sleep recordings during progressive MA titration. Long-term effectiveness, compliance and side effects of oral appliance (OA) in the titrated position were evaluated by questionnaires. Results: OA therapy was started at 80% of the maximum MA. Seventy percent of the patients had only one increment in MA with a marked decrease in mean AHI from 36 to 10. In the remaining cases, further increments in MA were associated with a progressive reduction in AHI and an increase in the number of patients responding to treatment. OA in the titrated position resulted in a 70% decrease in AHI, with 54% of patients showing complete responses, 29% partial responses and 17% no response. Daytime sleepiness and quality of life improved, too. Seventeen months after the start of treatment, 82% of the patients declared that they were still using OA almost all nights. Reported side effects including subjective occlusal changes were frequent but mild. Conclusions: Improvement in AHI during OA is dependent on the amount of MA. Sequential sleep recordings facilitate MA titration. Long-term MA therapy in the titrated position is effective and well tolerated. Reported side effects are frequent but mild.

High Baseline Insulin Levels Associated With 6-Year Incident Observed Sleep Apnea

OBJECTIVE Obstructive sleep apnea is common in patients with type 2 diabetes, and its association with insulin and insulin resistance has been examined in cross-sectional studies. We evaluate risk factors for incident observed sleep apnea in a general population not selected for sleep disturbances. RESEARCH DESIGN AND METHODS A total of 1,780 men and 1,785 women, aged 33 to 68 years, from the cohort Data from an Epidemiologic Study on the Insulin Resistance Syndrome (D.E.S.I.R.) responded to the question, “Has someone said to you that you stop breathing during your sleep?” at baseline and 6 years. Anthropometric, clinical, and biological factors were recorded at both time points. RESULTS At baseline, 14% of men and 7% of women reported having observed sleep apnea (positive response to question); 6-year incidences were 14 and 6%, respectively. Age, anthropometric parameters, blood pressure, and sleep characteristics were all associated with prevalent, observed apnea episodes, in both sexes. Baseline waist circumference was the strongest predictor of incident apnea: standardized odds ratio (OR), adjusted for age and sex, 1.34 (95% CI 1.19–1.52). After adjustment for age, sex, and waist circumference, the standardized ORs for incident observed apnea were identical for fasting insulin and the homeostasis model assessment of insulin resistance: 1.31 (1.13–1.51) and 1.24 (1.09–1.41) for triglycerides and 1.52 (1.12–2.05) for smoking. Observed apnea at baseline was not associated with changes in anthropometric or biological parameters over the 6-year follow-up. CONCLUSIONS The most important baseline risk factor for incident apnea was adiposity. After accounting for adiposity, other risk factors were high insulin, insulin resistance, high triglycerides, and smoking, factors amenable to lifestyle intervention.

Prévalence des symptômes du syndrome d'apnées du sommeil. Étude dans une population française d'âge moyen

Resume Objectif Determiner dans une large population francaise d’âge moyen, la prevalence des principaux symptomes du syndrome d’apnees du sommeil (SAS) et evaluer la proportion de sujets presentant l’association de plusieurs symptomes justifiant une exploration pendant le sommeil. Methodes Etude transversale chez 2 195 hommes et 2 247 femmes de 33 a 69 ans (cohorte DESIR) ayant rempli un autoquestionnaire « sommeil » et un autoquestionnaire general (sante, mode de vie). Resultats La prevalence des symptomes etait, chez les hommes et les femmes : ronflements (69 %, 46 %), somnolence diurne frequente (14 %, 18 %), apnees frequentes (5 %, 2 %). La forte suspicion de SAS (association de ronflements habituels avec somnolence diurne et/ou apnees) trouvee chez 8,5 % des hommes et 6,3 % des femmes, etait liee a l’âge, a l’index de masse corporelle, a une sante ressentie comme mediocre et a l’usage de tranquillisants ou de benzodiazepines. Chez les hommes, cette suspicion etait aussi liee a l’existence d’une hypertension et a la consommation d’alcool et de tabac. Conclusion Ronflements, somnolence diurne et apnees sont des symptomes frequents en population generale. L’association de ces symptomes, tres evocatrice de SAS et justifiant une exploration pendant le sommeil, est retrouvee chez 7,5 % de la population.

Influence of predicted FEV1 on bronchodilator response in asthmatic patients.

Background: There is currently disagreement on the way of expressing the reversibility of airflow obstruction, with some evaluations based on the initial FEV1 while others use predicted FEV1 (according to age, gender and height). Objectives: To test the relevance of expressing bronchodilator response as a percentage of predicted FEV1, we evaluated the influence of morphological data on the response to bronchodilators in a population with a large range of predicted values. Methods: We measured the change in FEV1 after inhalation of 200 µg of salbutamol in 30 asthmatic subjects (15 adults and 15 children) in whom predicted FEV1 ranged between 1.13 and 4.10 liters and analyzed the respective influence of initial and predicted FEV1 on bronchodilator response. Results: We have shown a significant relationship between the absolute variation in FEV1, in liters, and predicted FEV1 (p = 0.0019). There was also a significant relationship between the absolute variation in FEV1 and initial FEV1, in liters (p = 0.02). This relationship was no longer significant (p = 0.8) when the variation and initial FEV1 were both expressed as percentages of predicted FEV1. In addition, multiple regression analysis showed that predicted FEV1 was the only independent variable correlating with the response to bronchodilators. Conclusion: This study showed the influence of predicted FEV1 on bronchodilator response. This result provides an additional argument for expressing bronchodilator response as a percentage of predicted FEV1.

Traitement d’un kyste bronchogénique compressif par ponction sous tomodensitométrie

Resume Introduction Les kystes bronchogeniques sont des tumeurs mediastinales benignes dont le traitement de reference est la resection chirurgicale complete. Nous rapportons l’observation d’une patiente âgee, presentant un kyste bronchogenique symptomatique non operable, traite par ponction-aspiration sous controle tomodensitometrique. Cas clinique Une femme de 92 ans etait admise pour une dyspnee inspiratoire associee a un stridor. L’interrogatoire rapportait la decouverte d’une masse mediastinale laterotracheale droite, 2 ans auparavant. L’examen tomodensitometrique et l’endoscopie bronchique revelaient une compression tracheale par un volumineux kyste bronchogenique. La chirurgie etait contre-indiquee en raison de l’âge et des antecedents cardiaques de la patiente. Une ponction du kyste sous controle tomodensitometrique a permis d’evacuer 250 ml de liquide et de lever rapidement les signes de compression tracheale. La patiente est restee asymptomatique pendant plusieurs mois. L’operation a ete repetee un an plus tard du fait d’une recidive de la compression. Conclusion Cette observation souligne l’interet potentiel de la ponction sous controle tomodensitometrique en tant qu’alternative a la chirurgie en cas de kyste bronchogenique compressif inoperable.

Association Between Severity of Obstructive Sleep Apnea and Blood Markers of Liver Injury

Obstructive sleep apnea (OSA) may contribute to the development of nonalcoholic fatty liver disease. We performed a multisite cross-sectional study to evaluate the association between the severity of OSA and blood markers of liver steatosis (using the hepatic steatosis index), cytolysis (based on alanine aminotransferase activity), and significant liver fibrosis (based on the FibroMeter [Echosens] nonalcoholic fatty liver disease score) in 1285 patients with suspected OSA in France. After adjusting for confounders including central obesity, the risk of liver steatosis increased with the severity of OSA (P for trend < .0001) and sleep-related hypoxemia (P for trend < .0003 for mean oxygen saturation). Decreasing mean oxygen saturation during sleep also was associated independently with a higher risk of liver cytolysis (P for trend < .0048). Severe OSA conferred an approximate 2.5-fold increase in risk for significant liver fibrosis compared with patients without OSA, but the association between OSA severity and liver fibrosis was not maintained after adjusting for confounders.