Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline.

Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited.Target Audience: Patients with COPD, clinicians who care for them, and policy makers.Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.Recommendations:1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.

Eszopiclone increases the respiratory arousal threshold and lowers the apnoea/hypopnoea index in obstructive sleep apnoea patients with a low arousal threshold.

Recent insights into sleep apnoea pathogenesis reveal that a low respiratory arousal threshold (awaken easily) is important for many patients. As most patients experience stable breathing periods mediated by upper-airway dilator muscle activation via accumulation of respiratory stimuli, premature awakening may prevent respiratory stimuli build up as well as the resulting stabilization of sleep and breathing. The aim of the present physiological study was to determine the effects of a non-benzodiazepine sedative, eszopiclone, on the arousal threshold and the AHI (apnoea/hypopnoea index) in obstructive sleep apnoea patients. We hypothesized that eszopiclone would increase the arousal threshold and lower the AHI in patients with a low arousal threshold (0 to -15 cm H(2)O). Following a baseline overnight polysomnogram with an epiglottic pressure catheter to quantify the arousal threshold, 17 obstructive sleep apnoea patients, without major hypoxaemia [nadir SaO(2) (arterial blood oxygen saturation) >70%], returned on two additional nights and received 3 mg of eszopiclone or placebo immediately prior to each study. Compared with placebo, eszopiclone significantly increased the arousal threshold [-14.0 (-19.9 to -10.9) compared with -18.0 (-22.2 to -15.1) cm H(2)O; P<0.01], and sleep duration, improved sleep quality and lowered the AHI without respiratory event prolongation or worsening hypoxaemia. Among the eight patients identified as having a low arousal threshold, reductions in the AHI occurred invariably and were most pronounced (25±6 compared with 14±4 events/h of sleep; P<0.01). In conclusion, eszopiclone increases the arousal threshold and lowers the AHI in obstructive sleep apnoea patients that do not have marked overnight hypoxaemia. The greatest reductions in the AHI occurred in those with a low arousal threshold. The results of this single night physiological study suggest that certain sedatives may be of therapeutic benefit for a definable subgroup of patients. However, additional treatment strategies are probably required to achieve elimination of apnoea.

Obstructive sleep apnea and aging effects on macrovascular and microcirculatory function.

STUDY OBJECTIVES: Many patients with obstructive sleep apnea (OSA) are obese, and whether obesity itself explains the increased prevalence of cardiovascular disease in OSA is unknown. We hypothesize that OSA, independent of obesity, contributes to abnormal vascular function. DESIGN: Physiology study. SETTING: Academic medical centers. PATIENTS: Obese subjects, free of known comorbidities, were enrolled. MEASUREMENTS AND RESULTS: Vascular function was assessed with brachial artery ultrasound for flow-mediated dilation (FMD) and in skin microcirculation by laser Doppler flowmetry. Arterial stiffness was measured by arterial tonometry. Seventy-two subjects (43/72 women, 38/72 with OSA) were studied. FMD was impaired in patients with OSA, compared with control subjects (5.7% +/- 3.8% vs 8.3% +/- 4.1%, P = 0.005). In step-forward regression analysis inclusive of age, sex, and body mass index, age (P = 0.013) was a significant independent predictor of FMD. In a subgroup of subjects younger than 50 years of age (n = 59), however, OSA was the only independent predictor of FMD (P = 0.04), adjusted for known covariates. OSA did not significantly influence vascular function in the skin microcirculation. The augmentation index, a measure of arterial stiffness, was similar between the OSA and control groups (16.2% +/- 11.4% vs 20.4% +/- 10.1%, respectively, P = 0.10). In step-forward regression analysis of younger men (< or = 50 years old, 23 subjects), OSA independently predicted the augmentation index in men only (P = 0.001). CONCLUSIONS: In obesity, both OSA and aging impair endothelial function and increase arterial stiffness. The influence of OSA on vascular function is most pronounced in young subjects. OSA, therefore, may be associated with functional impairment ("a premature aging effect") on the endothelium and on arterial stiffness (in men), although skin microcirculatory function appears preserved.

Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea.

STUDY OBJECTIVES: Many patients with obstructive sleep apnea (OSA) have spontaneous periods of stable flow limited breathing during sleep without respiratory events or arousals. In addition, OSA is often more severe during REM than NREM and more severe during stage 2 than slow wave sleep (SWS). The physiological mechanisms for these observations are unknown. Thus we aimed to determine whether the activity of two upper airway dilator muscles (genioglossus and tensor palatini) or end-expiratory lung volume (EELV) differ between (1) spontaneously occurring stable and cyclical breathing and (2) different sleep stages in OSA. DESIGN: Physiologic observation. SETTING: Sleep physiology laboratory. STUDY PARTICIPANTS: 15 OSA patients with documented periods of spontaneous stable breathing. INTERVENTION: Subjects were instrumented with intramuscular electrodes for genioglossus and tensor palatini electromyograms (EMG(GG) and EMG(TP)), chest and abdominal magnetometers (EELV measurement), an epiglottic pressure catheter (respiratory effort), and a mask and pneumotachograph (airflow/ventilation). Patients slept supine overnight without CPAP. MEASUREMENTS AND RESULTS: Peak and Tonic EMG(GG) were significantly lower during cyclical (85.4 +/- 2.7 and 94.6 +/- 4.7 % total activity) than stable breathing (109.4 +/- 0.4 and 103 +/- 0.8% total activity, respectively). During respiratory events in REM, tonic EMG(GG) activity was lower than during respiratory events in stage 2 (71.9 +/- 5.1 and 119.6 +/- 5.6% total activity). EMG(GG) did not differ between stable stage 2 and stable SWS (98.9 +/- 3.2 versus 109.7 +/- 4.4% total activity), nor did EMG(TP) or EELV differ in any breathing condition/sleep stage. CONCLUSIONS: Increased genioglossus muscle tone is associated with spontaneous periods of stable flow limited breathing in the OSA subjects studied. Reductions in genioglossus activity during REM may explain the higher severity of OSA in that stage. Increased lung volume and tensor palatini activity do not appear to be major mechanisms enabling spontaneous stable flow limited breathing periods.

Effect of mild, asymptomatic obstructive sleep apnea on daytime heart rate variability and impedance cardiography measurements.

Dysregulation of autonomic nervous system dynamics is important in the pathophysiology of cardiovascular risk in obstructive sleep apnea (OSA). Heart rate variability (HRV) and impedance cardiography measures can estimate autonomic activity but have not gained traction clinically. The hypothesis of this study was that even in a cohort of patients with mild, asymptomatic OSA without overt cardiovascular disease, daytime HRV metrics and impedance cardiography measurements of preejection period would demonstrate increased sympathetic and decreased parasympathetic modulation compared to matched controls. Obese subjects (body mass index ≥30 kg/m(2)) without any known cardiovascular or inflammatory co-morbidities were recruited from the community. Subjects underwent standard in-laboratory polysomnography followed by simultaneous electrocardiographic and impedance cardiographic recordings while supine, supine with paced breathing, and after standing. Seventy-four subjects were studied, and 59% had OSA (apnea-hypopnea index ≥10 events/hour), with a median apnea-hypopnea index of 25.8 events/hour. Subjects with OSA had significantly decreased daytime time- and frequency-domain HRV indexes, but not significantly different preejection periods, compared to controls. Apnea-hypopnea index was a significant independent predictor of time-domain HRV measures in all awake conditions, after controlling for age, gender, blood pressure, fasting cholesterol levels and glycosylated hemoglobin. In conclusion, these results demonstrate reductions in cardiac vagal modulation, as measured by multiple daytime time-domain markers of HRV, in patients with asymptomatic OSA compared to controls. Further prospective outcomes-based studies are needed to evaluate the applicability of these metrics for noninvasive screening of obese patients with asymptomatic OSA, before the onset of overt cardiovascular disease.

Vascular dysfunction in obstructive sleep apnea and type 2 diabetes mellitus.

Despite the high prevalence of obstructive sleep apnea (OSA) in type 2 diabetes mellitus (DM), the attributable vascular risk from each condition is unknown. We hypothesize that OSA may have a similar effect on vascular function as type 2 diabetes does. Healthy normal-weight subjects, healthy obese subjects, subjects with type 2 diabetes, and obese subjects with OSA were enrolled. Vascular function was assessed with brachial artery ultrasound for flow-mediated dilatation (FMD) and in skin microcirculation by laser Doppler flowmetry. One hundred fifty-three subjects were studied: healthy normal-weight controls (NCs) (n = 14), healthy obese controls (OCs) (n = 33), subjects with DM (n = 68), and obese subjects with OSA (n = 38). The DM group did not undergo sleep study and thus may have had subclinical OSA. The OSA and type 2 diabetes groups had impaired FMD as compared to both the normal-weight and OC groups (5.8 ± 3.8%, 5.4 ± 1.6% vs. 9.1 ± 2.5%, 8.3 ± 5.1%, respectively, P < 0.001, post hoc Fischer test). When referenced to the NC group, a multiple linear regression model adjusting for covariates found that baseline brachial artery diameter (ß = -3.75, P < 0.001), OSA (ß = -2.45, P = 0.02) and type 2 diabetes status (ß = -2.31, P = 0.02), negatively predicted % FMD. OSA status did not seem to affect nitroglycerin-induced vasodilation (endothelium-independent) of the brachial artery or vascular function in the skin microcirculation. OSA impairs endothelial function in the brachial artery to a similar degree as type 2 diabetes does. OSA, however, does not appear to affect brachial endothelium-independent vasodilation or skin microcirculatory function. Treatment of OSA in patients with concomitant type 2 diabetes, therefore, may be a potential therapeutic option to improve macro-, but not microvascular outcomes.

A nonparametric surrogate-based test of significance for T-wave alternans detection.

We present a nonparametric adaptive surrogate test that allows for the differentiation of statistically significant T-wave alternans (TWA) from alternating patterns that can be solely explained by the statistics of noise. The proposed test is based on estimating the distribution of noise-induced alternating patterns in a beat sequence from a set of surrogate data derived from repeated reshuffling of the original beat sequence. Thus, in assessing the significance of the observed alternating patterns in the data, no assumptions are made about the underlying noise distribution. In addition, since the distribution of noise-induced alternans magnitudes is calculated separately for each sequence of beats within the analysis window, the method is robust to data nonstationarities in both noise and TWA. The proposed surrogate method for rejecting noise was compared to the standard noise-rejection methods used with the spectral method (SM) and the modified moving average (MMA) techniques. Using a previously described realistic multilead model of TWA and real physiological noise, we demonstrate the proposed approach that reduces false TWA detections while maintaining a lower missed TWA detection, compared with all the other methods tested. A simple averaging-based TWA estimation algorithm was coupled with the surrogate significance testing and was evaluated on three public databases: the Normal Sinus Rhythm Database, the Chronic Heart Failure Database, and the Sudden Cardiac Death Database. Differences in TWA amplitudes between each database were evaluated at matched heart rate (HR) intervals from 40 to 120 beats per minute (BPM). Using the two-sample Kolmogorov-Smirnov test, we found that significant differences in TWA levels exist between each patient group at all decades of HRs. The most-marked difference was generally found at higher HRs, and the new technique resulted in a larger margin of separability between patient populations than when the SM or MMA were applied to the same data.

The effect of increased genioglossus activity and end-expiratory lung volume on pharyngeal collapse.

Increasing either genioglossus muscle activity (GG) or end-expiratory lung volume (EELV) improves airway patency but not sufficiently for adequate treatment of obstructive sleep apnea (OSA) in most patients. The mechanisms by which these variables alter airway collapsibility likely differ, with increased GG causing airway dilation, whereas increased EELV may stiffen the airway walls through caudal traction. We sought to determine whether the airway stabilizing effect of GG activation is enhanced when EELV is increased. To investigate this aim, 15 continuous positive airway pressure (CPAP)-treated OSA patients were instrumented with an epiglottic catheter, intramuscular GG-EMG electrodes, magnetometers, and a nasal mask/pneumotachograph. Subjects slept supine in a sealed, head-out plastic chamber in which the extra-thoracic pressure could be lowered (to raise EELV) while on nasal CPAP with a variable deadspace to allow CO(2) stimulation (and GG activation). The pharyngeal critical closing pressure (P(CRIT)) was measured by sudden reduction of CPAP for three to five breaths each minute during non-rapid eye movement (NREM) sleep in 4 conditions: a) baseline, b) 500 ml increased EELV, c) 50% increased GG, and d) conditions b and c combined. P(CRIT) was found to be reduced from 2.2 + or - 0.7 cmH(2)O at baseline to -1.0 + or - 0.5 with increased EELV, 0.6 + or - 0.7 with increased GG and -1.6 + or - 0.7 when both variables were raised (P < 0.001). The slope of the P(CRIT) curves remained unchanged in all conditions (P = 0.05). However, the CPAP level at which flow limitation developed was lower in both increased EELV conditions (P = 0.001). These findings indicate that while both increased GG and EELV improve airway collapsibility, the combination of both variables has little additional effect over increasing EELV alone.