Nathalie Arnol

Noninvasive Ventilation in Mild Obesity Hypoventilation Syndrome: A Randomized Controlled Trial

OBJECTIVE Open studies suggest that treatment of obesity hypoventilation syndrome (OHS) by noninvasive ventilation (NIV) restores sleep quality and daytime vigilance and reduces cardiovascular morbidity. However, to our knowledge no randomized controlled trial (RCT) comparing NIV to conservative measures is available in the field. The goal of this study was to assess in patients with OHS, during an RCT, effects of 1-month NIV compared with lifestyle counseling on blood gas measurements, sleep quality, vigilance, and cardiovascular, metabolic, and inflammatory parameters. METHODS Thirty-five patients in whom OHS was newly diagnosed were randomized either to the NIV group or the control group represented by lifestyle counseling. Assessments included blood gas levels, subjective daytime sleepiness, metabolic parameters, inflammatory (hsCRP, leptin, regulated upon activation normal T-cell express and secreted [RANTES], monocyte chemoattractant protein-1, IL-6, IL-8, tumor necrosis factor-α, resistin) and antiinflammatory (adiponectin, IL-1-RA) cytokines, sleep studies, endothelial function (reactive hyperemia measured by peripheral arterial tonometry [RH-PAT]), and arterial stiffness. RESULTS Despite randomization, NIV group patients (n = 18) were older (58 ± 11 years vs 54 ± 6 years) with a higher baseline Paco(2) (47.9 ± 4.2 mm Hg vs 45.2 ± 3 mm Hg). In intention-to-treat analysis, compared with control group, NIV treatment significantly reduced daytime Paco(2) (difference between treatments: -3.5 mm Hg; 95% CI, -6.2 to -0.8) and apnea-hypopnea index (-40.3/h; 95% CI, -62.4 to -18.2). Sleep architecture was restored, although nonrespiratory microarousals increased (+9.4/h of sleep; 95% CI, 1.9-16.9), and daytime sleepiness was not completely normalized. Despite a dramatic improvement in sleep hypoxemia, glucidic and lipidic metabolism parameters as well as cytokine profiles did not vary significantly. Accordingly, neither RH-PAT (+0.02; 95% CI, -0.24 to 0.29) nor arterial stiffness (+0.22 m/s; 95% CI, -1.47 to 1.92) improved. CONCLUSIONS One month of NIV treatment, although improving sleep and blood gas measurements dramatically, did not change inflammatory, metabolic, and cardiovascular markers. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00603096; URL: www.clinicaltrials.gov.

Endothelial dysfunction and specific inflammation in obesity hypoventilation syndrome

Background Obesity hypoventilation syndrome (OHS) is associated with increased cardiovascular morbidity. What moderate chronic hypoventilation adds to obesity on systemic inflammation and endothelial dysfunction remains unknown. Question To compare inflammatory status and endothelial function in OHS versus eucapnic obese patients. Methodology 14 OHS and 39 eucapnic obese patients matched for BMI and age were compared. Diurnal blood gazes, overnight polysomnography and endothelial function, measured by reactive hyperemia peripheral arterial tonometry (RH-PAT), were assessed. Inflammatory (Leptin, RANTES, MCP-1, IL-6, IL-8, TNFα, Resistin) and anti-inflammatory (adiponectin, IL-1Ra) cytokines were measured by multiplex beads immunoassays. Principal Findings OHS exhibited a higher PaCO2, a lower forced vital capacity (FVC) and tended to have a lower PaO2 than eucapnic obese patients. HS-CRP, RANTES levels and glycated haemoglobin (HbA1c) were significantly increased in OHS (respectively 11.1±10.9 vs. 5.7±5.5 mg.l−1 for HS-CRP, 55.9±55.3 vs 23.3±15.8 ng/ml for RANTES and 7.3±4.3 vs 6.1±1.7 for HbA1c). Serum adiponectin was reduced in OHS (7606±2977 vs 13660±7854 ng/ml). Endothelial function was significantly more impaired in OHS (RH-PAT index: 0.22±0.06 vs 0.51±0.11). Conclusions Compared to eucapnic obesity, OHS is associated with a specific increase in the pro-atherosclerotic RANTES chemokine, a decrease in the anti-inflammatory adipokine adiponectin and impaired endothelial function. These three conditions are known to be strongly associated with an increased cardiovascular risk. Trial Registration ClinicalTrials.gov NCT00603096

Prognostic value of efficiently correcting nocturnal desaturations after one month of non-invasive ventilation in amyotrophic lateral sclerosis: A retrospective monocentre observational cohort study

Abstract NIV adherence (‘quantity’ of ventilation) has a prognostic impact in amyotrophic lateral sclerosis (ALS). We hypothesized that NIV effectiveness (‘quality’) could also have a similar impact. NIV effectiveness was evaluated in 82 patients within the first month (M1) and every three months (symptoms, arterial blood bases, and nocturnal pulsed oxygen saturation − SpO2). Kaplan-Meier survival and risk factors for mortality one year after NIV initiation were evaluated. Forty patients were considered ‘correctly ventilated’ at M1 (Group 1, less than 5% of nocturnal oximetry time with an SpO2<90% − TS90) while 42 were not (Group 2). Both groups were comparable in terms of respiratory and neurological baseline characteristics. Survival was better in Group 1 (75% survival at 12 months) than in Group 2 (43% survival at 12 months, p = 0.002). In 12 Group 2 patients corrective measures were efficient in correcting TS90 at six months. In this subgroup, one-year mortality was not different from that in Group 1. Multivariate analysis identified independent mortality risk factors expectedly including bulbar involvement (HR = 4.31 (1.73 − 10.76), p = 0.002), ‘rapid respiratory decline’ (HR = 3.55 (1.29 − 9.75), p = 0.014) and vital capacity (HR = 0.97 (0.95 − 0.99), p = 0.010), but also inadequate ventilation in the first month (HR = 2.32 (1.09 − 4.94), p = 0.029). In conclusion, in ALS patients NIV effectiveness to correct nocturnal desaturations is an independent prognostic factor.

Pleiotropic role of IGF-I in obesity hypoventilation syndrome

CONTEXT Obesity hypoventilation syndrome (OHS) is defined by the association between obesity and daytime arterial hypercapnia. The syndrome includes in variable proportion impaired diaphragmatic weakness, decreased central ventilatory drive and nearly systematically occurrence of sleep apnea. An increased cardio-vascular risk has been demonstrated compared to normocapnic obesity. IGF-I has a pleiotropic role in metabolism, ventilatory control, muscle function and cardiovascular protection. OBJECTIVES AND DESIGN We performed a case control study comparing somatotropic axis changes including IGF-I in obese with or without OHS. METHODS Patients underwent respiratory function tests, CO(2) ventilatory responses, polysomnography and somatotropic axis exploration (GH, IGF-I and IGFBP-3). RESULTS 15 OHS (BMI: 41+/-5.6 kg/m(2), PaCO(2): 6.13+/-0.39 kPa, age: 55.6+/-5.9 years) and 15 matched obese without hypercapnia (BMI: 42+/-6.7 kg/m(2), PaCO(2): 5.13+/-0.27 kPa, age: 55.0+/-7.5 years) were compared. IGF-I and IGFBP-3 were significantly lowered in OHS, and negatively correlated with PaCO(2) (r=-0.615; P<0.001 and r=-0.452; P=0.016, respectively). Inspiratory capacity and forced vital capacity reflecting respiratory muscle strength decreased significantly with IGF-I (r=0.408; P=0.038). Triglycerides levels were higher in OHS (1.64+/-0.58 versus 1.13+/-0.56 g/L; P<0.01), and negatively associated with IGF-I (r=-0.418; P=0.027). CONCLUSION A low IGF-I level is associated with hypercapnia presumably by reducing ventilatory drive and favouring muscle weakness. The relationship between increased triglycerides and low IGF-I may represent one of mechanisms involved in the OHS increased cardio-vascular risk.

Continuous Response of Optic Nerve Head Blood Flow to Increase of Arterial Blood Pressure in Humans

PURPOSE This study investigates the effect of increased ocular perfusion pressure (OPP) on optic nerve head (ONH) hemodynamics. METHODS In 21 healthy subjects, the increase in arterial blood pressure (BP), measured continuously using a pneumatic transcutaneous sensor, was produced by isometric exercise consisting of 2 minutes of hand-gripping. ONH blood flow parameters-namely the velocity (Vel), number (Vol), and flux (F) of red blood cells-were measured using the laser Doppler flowmeter (LDF). RESULTS In those 14 healthy subjects who exhibited a similar increase in BP to handgrip superior to 30% of baseline BP, group average increases of BP and OPP amounted to 34% ± 3% (SEM) and 43% ± 3%, respectively. The increase in F of 19% ± 8%, resulting from an increase in Vel (17% ± 7%) and Vol (6% ± 7%), was significantly less than predicted for a passive autoregulatory response, as revealed also by the increase in vascular resistance (R = OPP/F). Spearman test of linear correlations between F and time during handgrip led to the identification of one group of eight subjects (with a stable F) and one group of six subjects (with an increase in F). A closed-loop gain (G) of the regulatory process, defined as G = 1 - {(F - Fbl)/Fbl}/{(OPP - OPPbl)/OPPbl}, was found to be rather independent from the OPP, with an average value 0.7 ± 0.07. G was 0.83 ± 0.06 for the group of eight subjects with stable F and 0.3 ± 0.15 for the group of six subjects with F increasing with the OPP. CONCLUSIONS The continuous recording of both BP and LDFs represents a novel and more precise approach to the characterization of ONH hemodynamics during isometric exercise, especially useful in the future for patients with ocular diseases. The efficiency of the ONH blood flow autoregulation appears to vary significantly between healthy subjects. (ClinicalTrials.gov number, NCT00874913.).

Contemporary Reviews in Sleep MedicineFactors Contributing to Unintentional Leak During CPAP Treatment: A Systematic Review

&NA; CPAP is the first‐line treatment for moderate to severe OSA syndrome. Up to 25% of patients with OSA syndrome discontinue CPAP treatment due to side effects. Unintentional leakage and its associated annoying consequences are the most frequently reported adverse effects of CPAP. Successive technological improvements have not succeeded in addressing this issue. A systematic review was conducted (1) to assess the impact of different technological advances on unintentional leaks and (2) to determine if any patient characteristics have already been identified as determinants of unintentional leakage. No CPAP modality was superior to another in reducing unintentional leaks and, surprisingly, oronasal masks were associated with higher unintentional leaks. Nasal obstruction, older age, higher BMI, central fat distribution, and male sex might be associated with an increased risk of unintentional leakage. Such leaks remain an important problem. Further studies are needed to improve the understanding of underlying clinical factors so that patients at risk of unintentional leaks may be identified and individualized solutions applied.

Comparison of intraocular pressure measurements with the Reichert Pt100, the Keeler Pulsair Intellipuff portable noncontact tonometers, and Goldmann applanation tonometry.

Purpose:The aim of this study was to compare intraocular pressure (IOP) measurements using 2 portable tonometers, the Keeler Pulsair Intellipuff and the Reichert PT100, with Goldmann applanation tonometry (GAT). Materials and Methods:Prospective cross-sectional study was conducted on normotensive and hypertensive patients recruited from the outpatient clinic of the University Hospital of Grenoble. IOP was measured using 2 portable noncontact tonometers (NCTs) and GAT in one eye of each patient in a random order. Central corneal thickness was measured with the Accutome PachPen Pachymeter. The Wilcoxon and t tests were used to compare the differences between tonometers, the Pearson and the Spearman correlation tests to evaluate the correlation among the methods, and the Bland-Altman plots to evaluate the agreement among the methods. Intraclass correlation coefficient (ICC) was used to evaluate the agreement among the methods in normotensive and hypertensive patients separately. Results:A total of 137 eyes of 137 patients were included, 104 normotensive and 33 hypertensive eyes. We found an excellent agreement between PT100 and GAT (ICC=0.77) and between Intellipuff and GAT (ICC=0.75) in normotensive patients. We found a fair to good agreement (ICC=0.67) between PT100 and GAT in hypertensive patients. The agreement we found between Intellipuff and GAT was also excellent in hypertensive patients (ICC=0.86). Both NCTs significantly overestimated IOP measurements compared with GAT in normotensive and hypertensive eyes (mean of the differences between PT100 and GAT: 1.3±2.1 and 8.1±4.6 mm Hg in normotensive and in hypertensive patients, respectively (P<0.05), and between Pulsair Intellipuff and GAT: 1.5±1.8 and 2.3±4.8 mm Hg in normotensive and in hypertensive patients, respectively (P<0.05). Conclusions:The 2 NCTs agree well with GAT in normotensive patients. The Pulsair Intellipuff also agrees well with GAT in hypertensive patients.

Prevalence of obesity hypoventilation syndrome in ambulatory obese patients attending pathology laboratories

The prevalence of obesity hypoventilation syndrome (OHS) in the unselected obese is unknown. Our objectives were: (i) to determine the prevalence of OHS in ambulatory obese patients not previously referred to a pulmonologist for suspicion of sleep breathing disorders and (ii) to assess whether venous bicarbonate concentration [HCO3 − v] can be used to detect OHS.

Cysteinyl-leukotriene pathway as a new therapeutic target for the treatment of atherosclerosis related to obstructive sleep apnea syndrome

Graphical abstract Figure. No caption available. Aims: Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl‐leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA‐related atherosclerosis. Methods and results: Determinants of the urinary excretion of LTE4 (U‐LTE4) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136). Mechanisms linking IH, the CysLT pathway and atherogenesis were investigated in Apolipoprotein E deficient (ApoE−/−) mice exposed to 8‐week IH. In the whole cohort, U‐LTE4 was independently influenced by age, minimal oxygen saturation, and a history of cardiovascular events, and correlated significantly with intima‐media thickness. In the subgroup of OSA patients free of cardiovascular event, increased U‐LTE4 was increased compared to controls and independently related to hypoxia severity and traditional risk factors aggregated in the 10‐year cardiovascular risk score of European Society of Cardiology. In IH mice, atherosclerosis lesion size and mRNA levels of 5‐lipoxygenase, 5‐lipoxygenase activating protein (FLAP) and CysLT1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF‐1 to the FLAP promoter and was strongly associated with atherosclerosis lesion size. CysLT1 receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice. Conclusions: IH‐related CysLT pathway activation contributes to OSA‐induced atherogenesis. In the era of personalized medicine, U‐LTE4 may be a useful biomarker to identify OSA patients for whom CysLT1 blockade could represent a new therapeutic avenue for reducing cardiovascular risk.