Jean-Christian Borel

Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives

There are three major types of sleep-disordered breathing (SDB) with respect to prevalence and health consequences, i.e. obstructive sleep apnoea syndrome (OSAS), Cheyne–Stokes respiration and central sleep apnoea (CSR-CSA) in chronic heart failure, and obesity hypoventilation syndrome (OHS). In all three conditions, hypoxia appears to affect body functioning in different ways. Most of the molecular and cellular mechanisms that occur in response to SDB-related hypoxia remain unknown. In OSAS, an inflammatory cascade mainly dependent upon intermittent hypoxia has been described. There is a strong interaction between haemodynamic and inflammatory changes in promoting vascular remodelling. Moreover, during OSAS, most organ, tissue or functional impairment is related to the severity of nocturnal hypoxia. CSR-CSA occurring during heart failure is primarily a consequence of cardiac impairment. CSR-CSA has deleterious consequences for cardiac prognosis and mortality since it favours sympathetic activation, ventricular ectopy and atrial fibrillation. Although correction of CSR-CSA seems to be critical, there is a need to establish therapy guidelines in large randomised controlled trials. Finally, OHS is a growing health concern, owing to the worldwide obesity epidemic and OHS morbidities. The pathophysiology of OHS remains largely unknown. However, resistance to leptin, obesity and severe nocturnal hypoxia lead to insulin resistance and endothelial dysfunction. In addition, several adipokines may be triggered by hypoxia and explain, at least in part, OHS morbidity and mortality. Overall, chronic intermittent hypoxia appears to have specific genomic effects that differ notably from continuous hypoxia. Further research is required to fully elucidate the molecular and cellular mechanisms.

Nocturnal monitoring of home non-invasive ventilation: the contribution of simple tools such as pulse oximetry, capnography, built-in ventilator software and autonomic markers of sleep fragmentation

Complex respiratory events, which may have a detrimental effect on both quality of sleep and control of nocturnal hypoventilation, occur during sleep in patients treated with non-invasive ventilation (NIV). Among these events are patient-ventilator asynchrony, increases in upper airway resistance (with or without increased respiratory drive) and leaks. Detection of these events is important in order to select the most appropriate ventilator settings and interface. Simple tools can provide important information when monitoring NIV. Pulse oximetry is important to ensure that adequate oxygen saturation is provided and to detect either prolonged or short and recurrent desaturations. However, the specificity of pulse oximetry tracings during NIV is low. Transcutaneous capnography helps discriminate between hypoxaemia related to ventilation/perfusion mismatch and hypoventilation, documents correction of nocturnal hypoventilation and may detect ventilator-induced hyperventilation, a possible cause for central apnoea/hypopnoea and glottic closure. Data provided by ventilator software help the clinician by estimating ventilation, tidal volume, leaks and the rate of inspiratory or expiratory triggering by the patient, although further validation of these signals by independent studies is indicated. Finally, autonomic markers of sympathetic tone using signals such as pulse wave amplitude of the pulse oximetry signal can provide reliable information of sleep fragmentation.

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

Obesity hypoventilation syndrome: From sleep‐disordered breathing to systemic comorbidities and the need to offer combined treatment strategies

Obesity hypoventilation syndrome (OHS) is defined as a combination of obesity (body mass index ≥ 30 kg/m2), daytime hypercapnia (partial arterial carbon dioxide concentration ≥45 mm Hg) and sleep‐disordered breathing after ruling out other disorders that may cause alveolar hypoventilation. Through the prism of the International Classification of Functioning, OHS is a chronic condition associated with respiratory, metabolic, hormonal and cardiovascular impairments, leading to a decrease in daily life activities, a lack of social participation and high risk of hospitalization and death. Despite its severity, OHS is largely underdiagnosed and the health‐related costs are higher than those of apnoeic or obese eucapnic patients. The present review discusses the definition, epidemiology, physiopathology and treatment modalities of OHS. Although nocturnal positive airway pressure therapies represent first‐line treatment and are effective in improving patient outcomes, there is a need to offer combined treatment strategies and to assess the effect of multimodal therapeutic strategies on morbidity and mortality.

Significant Improvement in Arterial Stiffness After Endurance Training in Patients With COPD

BACKGROUND Arterial stiffness, a strong predictor of cardiovascular mortality, is abnormally elevated in patients with COPD. We investigated whether exercise training may decrease arterial stiffness in patients with COPD. METHODS Seventeen stable patients with COPD were included in this case-controlled study. Trained (n = 10) and untrained (n = 7) patients were matched for age (62 +/- 7 years), disease severity (FEV(1) = 50% +/- 17% predicted) and walking distance (412 +/- 70 m). Carotid-radial pulse wave velocity (PWV, a measure of arterial stiffness), pulmonary function, BP, plasmatic biomarkers, walking distance, and peripheral muscle function were evaluated in the two groups at baseline and after 4 weeks. In trained patients, aerobic capacity was also assessed during incremental exercise on a cycloergometer, before and after training. RESULTS Baseline PWV was similar between both groups. PWV was stable after 4 weeks in untrained patients with COPD, whereas it was reduced in trained patients (from 10.3 +/- 0.7 to 9.2 +/- 0.8 m/s, P = .001). PWV reduction correlated with improvements in walking distance (r = -0.49), muscle endurance (r = -0.48), systolic BP (r = 0.79), and fasting glucose (r = 0.59) in all patients (P < .05), and with changes in maximal heart rate and oxygen consumption (r = -0.70, P = .02) in trained patients. CONCLUSIONS Arterial stiffness appears to improve after exercise training in patients with COPD proportionally to changes in exercise capacity. Suggested mechanisms for arterial stiffness improvement are training-induced reductions in systolic BP and fasting glucose. TRIAL REGISTRATION clinicaltrials.gov; Identifier: NCT00404430.

Impact of Different Backup Respiratory Rates on the Efficacy of Noninvasive Positive Pressure Ventilation in Obesity Hypoventilation Syndrome: A Randomized Trial

BACKGROUND Unintentional leaks, patient-ventilatory asynchrony, and obstructive or central events (either residual or induced by noninvasive positive pressure ventilation [NPPV]) occur in patients treated with NPPV, but the impact of ventilator settings on these disturbances has been little explored. The objective of this study was to investigate the impact of backup respiratory rate (BURR) settings on the efficacy of ventilation, sleep structure, subjective sleep quality, and respiratory events in a group of patients with obesity hypoventilation syndrome (OHS). METHODS Ten stable patients with OHS treated with long-term nocturnal NPPV underwent polysomnographic recordings and transcutaneous capnography on 3 consecutive nights with three different settings for BURR in random order: spontaneous (S) mode, low BURR, and high BURR. No other ventilator parameter was modified. RESULTS The S mode was associated with the occurrence of a highly significant increase in respiratory events, mainly of central and mixed origin, when compared with both spontaneous/timed (S/T) modes. Accordingly, the oxygen desaturation index was significantly higher in the S mode than in either of the S/T modes. The results of nocturnal transcutaneous P(CO(2)) (Ptc(CO(2))) (mean value and time spent with Ptc(CO(2)) > 50 mm Hg) were similar over the three consecutive nocturnal recordings. The quality of sleep was perceived as slightly better, and the number of perceived arousals as lower with the low- vs high-BURR (S/T) mode. CONCLUSIONS In a homogenous group of patients treated with long-term NPPV for obesity-hypoventilation, changing BURR from an S/T mode with a high or low BURR to an S mode was associated with the occurrence of a highly significant increase in respiratory events, of mainly central and mixed origin. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01130090; URL: www.clinicaltrials.gov

Nonalcoholic Fatty Liver Disease, Nocturnal Hypoxia, and Endothelial Function in Patients With Sleep Apnea

BACKGROUND Nocturnal hypoxia, the hallmark of OSA, is a potential contributing factor for nonalcoholic fatty liver disease (NAFLD). NAFLD severity and its implication in OSA-related endothelial dysfunction have not been investigated in a large, unselected OSA population, including nonobese subjects. METHODS Noninvasive blood tests (SteatoTest, NashTest, and FibroTest) were used to evaluate steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis in a large cohort of patients with OSA. In the same group, endothelial function and its links with NAFLD severity were assessed. RESULTS Of the 226 subjects included who were referred for suspicion of OSA (men, 55%; median age, 56 years; median BMI, 34.2 kg/m2 [33% with BMI<30 kg/m2]), 61.5% exhibited moderate or severe steatosis. By multivariate analysis, independent factors for liver steatosis were, as expected, triglyceride levels (P<.0001) and insulin resistance (P=.0004) as well as nocturnal cumulative time spent<90% of oxygen saturation (CT90) (P=.01). Thirty-eight percent had borderline or possible NASH (N1 or N2 with NashTest). CT90 was significantly associated with borderline or possible NASH (P=.035) in univariate but not in multivariate analysis. The dose-response relationship between the severity of nocturnal hypoxia and liver injury was established only in morbid obesity and not in lean. Multivariate models showed that steatosis was independently associated with endothelial dysfunction after adjustment for confounders. CONCLUSIONS In a large, unselected OSA population, the severity of nocturnal hypoxia was independently associated with steatosis. Preexisting obesity exacerbated the effects of nocturnal hypoxemia. NAFLD is a potential mechanism of endothelial dysfunction in OSA.

Comorbidities and Mortality in Hypercapnic Obese under Domiciliary Noninvasive Ventilation

Background The higher mortality rate in untreated patients with obesity-associated hypoventilation is a strong rationale for long-term noninvasive ventilation (NIV). The impacts of comorbidities, medications and NIV compliance on survival of these patients remain largely unexplored. Methods Observational cohort of hypercapnic obese patients initiated on NIV between March 2003 and July 2008. Survival curves were estimated by the Kaplan–Meier method. Anthropometric measurements, pulmonary function, blood gases, nocturnal SpO2 indices, comorbidities, medications, conditions of NIV initiation and NIV compliance were used as covariates. Univariate and multivariate Cox models allowed to assess predictive factors of mortality. Results One hundred and seven patients (56% women), in whom NIV was initiated in acute (36%) or chronic conditions, were followed during 43±14 months. The 1, 2, 3 years survival rates were 99%, 94%, and 89%, respectively. In univariate analysis, death was associated with older age (>61 years), low FEV1 (<66% predicted value), male gender, BMI×time, concomitant COPD, NIV initiation in acute condition, use of inhaled corticosteroids, ß-blockers, nonthiazide diuretics, angiotensin-converting enzyme inhibitors and combination of cardiovascular drugs (one diuretic and at least one other cardiovascular agent). In multivariate analysis, combination of cardiovascular agents was the only factor independently associated with higher risk of death (HR = 5.3; 95% CI 1.18; 23.9). Female gender was associated with lower risk of death. Conclusion Cardiovascular comorbidities represent the main factor predicting mortality in patient with obesity-associated hypoventilation treated by NIV. In this population, NIV should be associated with a combination of treatment modalities to reduce cardiovascular risk.

A critical review of peripheral arterial tone and pulse transit time as indirect diagnostic methods for detecting sleep disordered breathing and characterizing sleep structure

Purpose of review Sympathetic activity varies continuously across sleep stages. During rapid eye movement sleep, sympathetic tone increases substantially but is highly variable. Microarousals are associated with momentary bursts of sympathetic activity. Abnormal respiratory events progressively elevate sympathetic activity in proportion to the severity of oxyhemoglobin desaturation. These phenomena imply that cardiovascular markers of sympathetic activity such as peripheral arterial tone (PAT) and pulse transit time could be indirect tools for diagnosing sleep disordered breathing and characterizing sleep structure and fragmentation. Recent findings Measurement of variations in PAT coupled with pulse rate accelerations and desaturations in oximetry can be used to diagnose sleep apnea. Good agreement between both manually and automatically analyzed PAT recordings and polysomnography has been demonstrated during in-laboratory or at-home studies. Numerous validation studies against esophageal pressure have demonstrated that pulse transit time is the best noninvasive method for measurement of respiratory effort. Pulse transit time and PAT are sensitive techniques for arousal recognition, particularly in children and infants. There are specific sleep stage-dependent PAT patterns that allow for the recognition of rapid eye movement sleep and, in the case of nonrapid eye movement sleep, the separation of lighter stages from deeper, slow wave sleep. Elevated nocturnal sympathetic activity as documented by PAT attenuations is linked with chronically elevated blood pressure in humans. Summary Cardiovascular markers of autonomic control during sleep permit not only the diagnosis of obstructive sleep apnea and estimation of sleep structure but are also linked with the prevalence of daytime hypertension.