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.

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.

Effects of diabetes and obesity on vascular reactivity, inflammatory cytokines, and growth factors.

We examined the influences of obesity and diabetes on endothelium-dependent and -independent vasodilation, inflammatory cytokines, and growth factors. We included 258 subjects, age 21-80 years in four groups matched for age and gender: 40 healthy nonobese (BMI <30 kg·m(-2)) nondiabetic subjects, 76 nonobese diabetic patients, 37 obese (BMI >30) nondiabetic subjects, and 105 obese (BMI >30) diabetic patients. The flow-mediated dilation (FMD, endothelium-dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) in the brachial artery, the vascular reactivity at the forearm skin and serum growth factors and inflammatory cytokines were measured. FMD was reduced in the nonobese diabetic patients, obese nondiabetic controls, and obese diabetic patients (P < 0.0001). NID was different among all four groups, being highest in the obese nondiabetic subjects and lowest in the obese diabetic patients (P < 0.0001). The resting skin forearm blood flow was reduced in the obese nondiabetic subjects (P < 0.01). Vascular endothelial growth factor (VEGF) was higher in the obese nondiabetic subjects (P < 0.05), tumor necrosis factor-α was higher in the obese diabetic patients (P < 0.0001) and C-reactive protein was higher in both the obese nondiabetic and diabetic subjects (P < 0.0001). Soluble intercellular adhesion molecule-1 was elevated in the two diabetic groups and the obese nondiabetic subjects (P < 0.05). We conclude that diabetes and obesity affect equally the endothelial cell function but the smooth muscle cell function is affected only by diabetes. In addition, the above findings may be related to differences that were observed in the growth factors and inflammatory cytokines.

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.

The influence of intermittent hypoxemia on platelet activation in obese patients with obstructive sleep apnea.

OBJECTIVES: Literature regarding platelet function in obstructive sleep apnea (OSA) has considerable limitations. Given the central role of platelets in atherothrombosis and the known cardiovascular risk of OSA, we hypothesized that OSA severity is predictive of platelet function, independent of known comorbidities. DESIGN: Obese subjects, without comorbidities, underwent overnight, in-lab polysomnography. The following morning, 5 biomarkers of platelet activation were measured by whole-blood flow cytometry at baseline and in response to agonists (no stimulation, stimulation with 5 µM ADP agonist, and stimulation with 20 µM ADP agonist): platelet surface P-selectin, activated glycoprotein (GP) IIb/IIIa, and GPIb receptor expression, platelet-monocyte aggregation (PMA) and platelet-neutrophil aggregation (PNA). RESULTS: Of the 77 subjects, 47 were diagnosed with OSA (median apnea-hypopnea index [AHI] of 24.7 ± 28.1/h in subjects with OSA and 3.0 ± 3.9/h in subjects without OSA, p < 0.001). The groups were matched for body mass index, with a mean body mass index of 40.3 ± 9.6 kg/m(2) in subjects with OSA and 38.9 ± 6.0 kg/m(2) in subjects without OSA (p = 0.48). A comparison of time spent with an oxygen saturation of less than 90% showed that subjects who had 1 minute or more of desaturation time per hour of sleep had lower GPIb fluorescence in circulating platelets, as compared with those subjects who had less than 1 minute of desaturation time per hour of sleep; similar findings were observed following 5 µM and 20 µM of ADP stimulation, as compared with control vehicle, suggesting higher levels of circulating platelet activity. In multivariate analyses, only nocturnal hypoxemia and female sex predicted agonist response. Platelet surface P-selectin, platelet surface-activated GPIIb/IIIa, PMA, and PNA were not significantly correlated with markers of OSA. CONCLUSIONS: In obese patients with OSA, platelet activation is associated with greater levels of oxygen desaturation, compared with matched control subjects. Metrics other than AHI (e.g., hypoxemia) may determine OSA-related thrombotic risk.

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.

Therapeutic interventions and oxidative stress in diabetes.

Many therapeutic agents that are used in patients with diabetes mitigate oxidative stress. These agents are of particular interest because oxidative stress is elevated in diabetes and is thought to contribute to vascular dysfunction. Agents that merely quench already formed reactive oxygen species have demonstrated limited success in improving cardiovascular outcomes. Thus, although vitamin E, C, and alpha lipoic acid appeared promising in animal models and initial human studies, subsequent larger trials have failed to demonstrate improvement in cardiovascular outcomes. Drugs that limit the production of oxidative stress are more successful in improving vascular outcomes in patients with diabetes. Thus, although statins, ACE inhibitors, ARBs and thiazolinediones are used for varied clinical purposes, their increased efficacy in improving cardiovascular outcomes is likely related to their success in reducing the production of reactive oxygen species at an earlier part of the cascade, thereby more effectively decreasing the oxidative stress burden. In particular, statins and ACE inhibitors/ ARBs appear the most successful at reducing oxidative stress and vascular disease and have potential for synergistic effects.

Total serum bilirubin does not affect vascular reactivity in patients with diabetes.

Bilirubin may have a major role in the prevention of cardiovascular disease based on recent data regarding its anti-oxidant properties. We determined the relationship between total serum bilirubin and vascular reactivity in a large cohort of individuals with diabetes, a disease associated with known oxidant stress. We studied 302 individuals: 52 controls, 37 with type 1 diabetes, 213 with type 2 diabetes. High-resolution ultrasound was used to measure flow-mediated dilation (FMD; endothelium-dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) of the brachial artery. Laser Doppler perfusion imaging was used to measure microvascular reactivity in the forearm skin before and after iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent). Bilirubin levels were higher in the type 2 diabetes group (0.71 +/- 0.34 mg/dl) compared to controls (0.56 +/- 0.26 mg/dl, p < 0.0001). A weak inverse correlation was observed between bilirubin and FMD (r = -0.125, p = 0.032) and skin endothelium-dependent vasodilation (r = -0.157, p = 0.019). In multivariate analyses, however, these correlations were not statistically significant. There is no association between bilirubin levels and vascular reactivity in the macro- and microcirculation of individuals with diabetes. Bilirubin, therefore, does not correlate with predictors of cardiovascular risk in the diabetic population.

Preferential migration of T regulatory cells induced by IL-16.

As a natural ligand for CD4, IL-16 has been shown to preferentially induce migration in Th1 cells, and, in long-term cultures with IL-2, IL-16 facilitates the expansion of CD4(+)CD25(+) cells. In addition, IL-16 has an immunomodulatory role in asthmatic inflammation, as exogenous administration significantly reduces inflammation and airway hyperreactivity. The mechanism for this, however, is not clear. Based on its functional characteristics and potential immunomodulatory role, we investigated the ability of IL-16 to recruit and influence the development of T regulatory (Treg) cells. We now demonstrate that IL-16 preferentially induces migration in a CD25(+)CTLA-4(+) human T cell subset and that responding cells produce IFNgamma and TGFbeta but not IL-10. These cells are relatively unresponsive to antigenic stimulation and can suppress proliferation and IL-5, but not IFNgamma, production by autologous T cells. We further demonstrate that IL-16-recruited cells are enriched for Forkhead box P3 (Foxp3). In addition, we find that IL-16 stimulation may facilitate de novo induction of Foxp3(+) Treg cells, because the stimulation of FoxP3-negative T cells for 48 h results in the expression of FoxP3 mRNA and protein. These data indicate that at sites of inflammation IL-16 may contribute to selective Treg cell expansion through the preferential induction of a migratory response from existing Treg cells, as well as by the induction of de novo generation of FoxP3(+) cells. These findings offer a potential mechanism for the immunosuppressive effects of IL-16 seen in Th2-mediated inflammation.

Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol.

Previous work has shown that IL-16/CD4 induces desensitization of both CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16 interaction with CD4 on CXCR3-induced migration. In this study we demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on primary human T cells. IL-16/CD4 stimulation does not result in surface modulation of CXCR3 or changes in CXCL10 binding affinity. This effect does require p56(lck) enzymatic activity and the presence of CCR5, because desensitization is not transmitted in the absence of CCR5. Treatment of human T cells with methyl-beta-cyclodextrin, a cholesterol chelator, prevented the desensitization of CXCR3 via IL-16/CD4, which was restored after reloading of cholesterol, indicating a requirement for intact cholesterol. These studies demonstrate an intimate functional relationship among CD4, CCR5, and CXCR3, in which CCR5 can act as an adaptor molecule for CD4 signaling. This process of regulating Th1 cell chemoattraction may represent a mechanism for orchestrating cell recruitment in Th1-mediated diseases.

Regulation of nuclear Prointerleukin-16 and p27(Kip1) in primary human T lymphocytes.

Prointerleukin-16 (Pro-IL-16) is an abundant, PDZ domain-containing protein expressed in the nucleus and cytoplasm of resting human T lymphocytes. We have previously shown that ectopic expression of Pro-IL-16 in Pro-IL-16-negative human Jurkat cells represses transcription of the F-box protein, Skp2, resulting in accumulation of the cyclin-dependent kinase inhibitor, p27(Kip1), and G0/G1 cell cycle arrest. The current studies demonstrate the kinetics of Pro-IL-16 and p27(Kip1) expression in activated normal human T lymphocytes. We correlate nuclear Pro-IL-16 loss with decreased p27(Kip1) expression, increased cell cycle progression, and proliferation. Conversely, we show that constitutive expression of Pro-IL-16 by retroviral infection of activated human T lymphocytes induces G0/G1 cell cycle arrest, inhibits proliferation, and is associated with increased levels of p27(Kip1). These findings implicate nuclear Pro-IL-16 as a cell cycle regulatory protein for human T lymphocytes.