F. Gagnadoux

Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome

The aim of this cross-sectional study was to evaluate the frequency of type‐2 diabetes and impaired glucose tolerance (IGT) in a large clinic-based male population presenting various degrees of obstructive sleep apnoea syndrome (OSAS) and to analyse the relationship between OSAS and glucose-insulin metabolism. Male patients (n=595) with suspected OSAS underwent both nocturnal polysomnography and a 2‐h oral glucose-tolerance test with measurements of fasting and postload blood glucose and plasma insulin. Insulin sensitivity was evaluated by the ratio of fasting glucose to fasting insulin. OSAS was diagnosed in 494 patients, while 101 patients were nonapnoeic snorers. Type‐2 diabetes was present in 30.1% of OSAS patients and 13.9% of nonapnoeic snorers. IGT was diagnosed in 20.0% of OSAS patients and 13.9% of nonapnoeic snorers. Fasting and postload blood glucose increased with severity of sleep apnoea. Insulin sensitivity decreased with increasing severity of sleep apnoea. In addition to body mass index and age, the apnoea/hypopnoea index independently influenced postload blood glucose and insulin sensitivity. The authors conclude that in a clinic-based sample of patients, obstructive sleep apnoea syndrome is associated with a high frequency of type‐2 diabetes and impaired glucose tolerance. The relationship between sleep-disordered breathing and impaired glucose-insulin metabolism is independent of obesity and age.

Chronic liver injury during obstructive sleep apnea

Patients with obstructive sleep apnea (OSA) are at risk for the development of fatty liver as a result of being overweight. Several data suggest that OSA per se could be a risk factor of liver injury; ischemic hepatitis during OSA has been reported, and OSA is an independent risk factor for insulin resistance. Therefore, we investigated liver damage and potential mechanisms in 163 consecutive nondrinking patients with nocturnal polysomnographic recording for clinical suspicion of OSA. Serum levels of liver enzymes were measured in all patients. Liver biopsy was offered to patients with elevated liver enzymes. Intrahepatic hypoxia was assessed by the expression of vascular endothelial growth factor (VEGF) on liver biopsy specimens. Severe OSA (apnea‐hypopnea index [AHI] > 50/hr) was seen in 27% of patients; 52% had moderate OSA (AHI 10‐50/hr), and 21% had no OSA. Overall, 20% had elevated liver enzymes. Independent parameters associated with elevated liver enzymes were body mass index (BMI) (OR: 1.13; CI: 1.03‐1.2) and severe OSA (OR: 5.9; CI: 1.2‐29). Liver biopsy was performed in 18 of 32 patients with elevated liver enzymes and showed steatohepatitis in 12 cases, associated with fibrosis in 7 cases. Patients with severe OSA were more insulin‐resistant according to homeostasis model assessment, had higher percentage of steatosis as well as scores of necrosis and fibrosis, despite similar BMI. Hepatic immunostaining used as an indirect marker of hypoxia was not different between patients with or without severe OSA. In conclusion, severe OSA is a risk factor for elevated liver enzymes and steatohepatitis independent of body weight. Promotion of insulin resistance is probably involved. Further studies are needed to determine whether hypoxia contributes directly to liver injury. (HEPATOLOGY 2005;41:1290–1296.)

Titrated mandibular advancement versus positive airway pressure for sleep apnoea

The aim of this study was to compare mandibular advancement device (MAd) therapy and continuous positive airway pressure (CPAP) for obstructive sleep apnoea/hypopnoea syndrome (OSAHS) after one-night polysomnographic (PSG) titration of both treatments. 59 OSAHS patients (apnoea/hypopnoea index (AHI): 34±13 events·h−1; Epworth scale: 10.6±4.5) were included in a crossover trial of 8 weeks of MAd and 8 weeks of CPAP after effective titration. Outcome measurements included home sleep study, sleepiness, health-related quality of life (HRQoL), cognitive tests, side-effects, compliance and preference. The median (interquartile range) AHI was 2 (1–8) events·h−1 with CPAP and 6 (3–14) events·h−1 with MAd (p<0.001). Positive and negative predictive values of MAd titration PSG for treatment success were 85% and 45%, respectively. Both treatments significantly improved subjective and objective sleepiness, cognitive tests and HRQoL. The reported compliance was higher for MAd (p<0.001) with >70% of patients preferring this treatment. These results support titrated MAd as an effective therapy in moderately sleepy and overweight OSAHS patients. Although less effective than CPAP, successfully titrated MAd was very effective at reducing the AHI and was associated with a higher reported compliance. Both treatments improved functional outcomes to a similar degree. One-night titration of MAd had a low negative predictive value for treatment success.

Oral Appliance Treatment for Obstructive Sleep Apnea: An Update

Oral appliances (OA) have emerged as an alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA) treatment. The most commonly used OA reduces upper airway collapse by advancing the mandible (OAm). There is a strong evidence base demonstrating OAm improve OSA in the majority of patients, including some with more severe disease. However OAm are not efficacious for all, with approximately one-third of patients experiencing no therapeutic benefit. OAm are generally well tolerated, although short-term adverse effects during acclimatization are common. Long-term dental changes do occur, but these are for the most part subclinical and do not preclude continued use. Patients often prefer OAm to gold-standard CPAP treatment. Head-to-head trials confirm CPAP is superior in reducing OSA parameters on polysomnography; however, this greater efficacy does not necessarily translate into better health outcomes in clinical practice. Comparable effectiveness of OAm and CPAP has been attributed to higher reported nightly use of OAm, suggesting that inferiority in reducing apneic events may be counteracted by greater treatment adherence. Recently, significant advances in commercially available OAm technologies have been made. Remotely controlled mandibular positioners have the potential to identify treatment responders and the level of therapeutic advancement required in single night titration polysomnography. Objective monitoring of OAm adherence using small embedded temperature sensing data loggers is now available and will enhance clinical practice and research. These technologies will further enhance efficacy and effectiveness of OAm treatment for OSA.

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.

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.

Economic arguments for the immediate management of moderate-to-severe obstructive sleep apnoea syndrome

The objective of this study was to measure the impact of a 6‐month delay in the diagnosis and treatment of patients with moderate obstructive sleep apnoea syndrome (OSAS) (apnoea/hypopnoea index (AHI) <30) or severe OSAS (AHI ≥30) on daytime sleepiness, cognitive functions, quality of life and healthcare expenditure (hospitalisations, medical visits, complementary tests, biological tests and drug prescriptions). In addition, this study aimed to analyse the incremental cost effectiveness ratios related to daytime sleepiness or quality of life following immediate introduction of treatment in these two populations. This study was conducted as a multicentre randomised controlled trial and carried out at two teaching hospitals in France. A total of 171 patients were followed for 6 months, with 82 patients randomised to group 1 “immediate polysomnography” and 89 in group 2 “polysomnography within 6 months”. Patients with severe OSAS were deprived of a significant improvement of their daytime sleepiness (5.1±5.0 at the Epworth Sleepiness Scale score in group 1 versus 0.2±3.4 in group 2) and quality of life (12.4±13.3 at the Nottingham Health Profile score in group 1 versus 0.7±10.1 in group 2) during the waiting time. The impact of delayed management in subjects with less severe OSAS only concerned daytime sleepiness (1.9±3.3 in group 1 versus 0.3±4.3 in group 2). Delayed treatment did not affect cognitive functions or healthcare expenditure regardless of the severity of the disease. Incremental cost effectiveness ratios related to rapid introduction of treatment were significantly lower in the patients with more severe OSAS. These results provide fairly clear medical and economic arguments in favour of early management of patients with more severe forms of obstructive sleep apnoea syndrome.

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.

Influence of Marital Status and Employment Status on Long-Term Adherence with Continuous Positive Airway Pressure in Sleep Apnea Patients

Background Long-term adherence is a major issue in patients receiving home continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea-hypopnea syndrome (OSAHS). In a multicenter prospective cohort (the Institut de Recherche en Santé Respiratoire des Pays de la Loire [IRSR] sleep cohort) of consecutive OSAHS patients in whom CPAP had been prescribed for at least 90 days, we studied the impact on long-term treatment adherence of socioeconomic factors, patients and disease characteristics prior to CPAP initiation. Methods and Principal Findings Among 1,141 patients in whom CPAP had been prescribed for an average of 504±251 days (range: 91 to 1035), 674 (59%) were adherent with a mean daily use of CPAP≥4 h (mean: 6.42±1.35 h). Stepwise regression analysis identified 4 independent factors of CPAP adherence including apnea-hypopnea index (AHI) (OR: 1.549, 95%CI 1.163 to 2.062 for AHI≥30 vs. AHI<30; p = 0.003), body mass index (BMI) (OR: 1.786, 95%CI 1.131 to 2.822 for BMI≥25 and <30 kg/m2, p = 0.01; OR: 1.768, 95%CI 1.145–2.731 for BMI≥30 kg/m2, p = 0.01 vs. BMI<25 kg/m2), employment status (OR: 1.414, 95%CI 1.097–1.821 for retired vs. employed; p = 0.007) and marital status (OR: 1.482, 95%CI 1.088–2.019 for married or living as a couple vs. living alone; p = 0.01). Age, gender, Epworth sleepiness scale, depressive syndrome, associated cardiovascular morbidities, educational attainment and occupation category did not influence CPAP adherence. Conclusions Marital status and employment status are independent factors of CPAP adherence in addition to BMI and disease severity. Patients living alone and/or working patients are at greater risk of non-adherence, whereas adherence is higher in married and retired patients. These findings suggest that the social context of daily life should be taken into account in risk screening for CPAP non-adherence. Future interventional studies targeting at-risk patients should be designed to address social motivating factors and work-related barriers to CPAP adherence.

Aerosol delivery of chemotherapy in an orthotopic model of lung cancer

The aim of this study was to evaluate the effect on tumour growth of gemcitabine delivered by aerosol in an orthotopic model of lung carcinoma. Large cell carcinoma (NCI-H460) cells were implanted intrabronchially in 24 male BALB/c nude mice on day (d) 0. Aerosols were delivered once a week from d1 to d29 using an endotracheal sprayer. Altogether, 16 animals received gemcitabine at 8 (n = 8) and 12 mg·kg−1 (n = 8), and eight received a vehicle aerosol. Animals were sacrificed on d36 for histological examination. All animals in the vehicle group developed a large infiltrating carcinoma. Comparatively, four of 13 (31%) animals treated with gemcitabine had no visible tumour and nine of 13 (69%) had a smaller carcinoma with a mean±sem largest tumour diameter of 2.05±0.7 versus 5±0.3 mm in the vehicle group. Gemcitabine was well tolerated at 8 mg·kg−1. At 12 mg·kg−1, three cases of fatal pulmonary oedema were observed, prompting a dose reduction to 8 mg·kg−1 in the remaining animals. A dose effect was observed, with more marked tumour growth inhibition in the animals treated at 12 mg·kg−1 on d1 and d8. In conclusion, in this study, an animal model of aerosolised chemotherapy in lung cancer was developed and demonstrated inhibition of orthotopic tumour growth by aerosol delivery of gemcitabine.