Susie Yim-Yeh

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.

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.

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 (β = −3.75, P < 0.001), OSA (β = −2.45, P = 0.02) and type 2 diabetes status (β = −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.

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.

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.

Carbon Monoxide Poisoning, or Carbon Monoxide Protection?

Carbon monoxide (CO) is a molecule generally presumed to be deleterious when inhaled at high concentrations, but is a marker of oxidative stress and inflammation when endogenously produced. Many reports1–3 have focused on increased endogenous CO production in pulmonary diseases, including asthma, COPD, acute pneumonia, and ARDS. In this issue of CHEST (see page 904), Kobayashi and colleagues4 add obstructive sleep apnea (OSA) to the list. In documented nonsmokers with OSA and control subjects, CO levels were measured before and after polysomnography. Although CO levels were similar in OSA patients and control subjects prior to sleep, those patients with OSA had elevations in venous CO level after sleep. Moreover, the nocturnal change in CO correlated modestly with the apnea-hypopnea index and duration of hypoxemia during sleep. Treatment with continuous positive airway pressure (CPAP) in some of these patients attenuated the rise in CO, so that treated OSA patients had no difference in CO when compared to control subjects. Linking OSA to cardiovascular morbidity, the authors conclude that “normalization of venous CO levels by CPAP therapy can potentially reduce the risk of disease associated cardiovascular events.” The authors also found concentrations of indirect bilirubin to be elevated after sleep in patients with OSA, suggesting that the sleep-related increase in CO is due to the induction of the heme oxygenase (HO) system. CO can be produced endogenously by the breakdown of heme into CO, biliverdin (subsequently degraded to bilirubin), and iron by HO.5 There are constitutively active isoforms of HO, but HO-1 is inducible and its byproduct CO has been suggested as a marker of the activity of the enzyme. HO was initially thought to have only a “housekeeping” role (ie, scavenging and breaking down free heme). However, several other observations suggested that it might have greater importance. For example, HO has a conserved structure across species (even those without circulating heme), it exists in organs not thought to play a role in heme degradation, and, most importantly, its function can be induced by cellular stressors such as inflammation and infection. The HO products CO and bilirubin are now understood to be mediators and effectors that promote cytoprotection via antiinflammatory, antiapoptotic, and antiproliferative effects, and also invoke antioxidant responses. Thus, the HO system is now thought to be protective from a variety of cellular insults. HO-1 is induced ubiquitously in most cell types with high levels of expression in lung endothelial cells, fibroblasts, airway epithelial cells, inflammatory cells, and type II pneumoctyes. Differences between the arterial and venous CO levels suggest that the lungs produce a significant proportion of all endogenous CO.6 HO-1 can be induced by various stimuli, including hyperoxia, inflammatory cytokines such as interleukin-6, and hypoxia. Continuous hypoxia has been extensively studied as it provides a good model for the protective effects of HO. Mice exposed to hypoxia produce inflammatory cytokines and chemokines, then develop pulmonary hypertension. However, hypoxia also up-regulates transcription of the HO-1 gene, and increases CO and bilirubin production. The HO products counteract the acute effects of hypoxia. CO is a potent vasodilator, and bilirubin acts as an antioxidant against reactive oxygen species. In fact, transgenic mice overexpressing HO-1 are protected against both pulmonary inflammation and pulmonary hypertension, while HO-1 null mice have a maladaptive response to hypoxia and subsequent pulmonary hypertension.7,8 In this light, the induction of the HO system and the generation of CO is likely a protective response to the stress of OSA, rather than a causative mechanism of cardiovascular morbidity. This was the conclusion reached by Chin et al9 who found higher morning bilirubin levels in patients with OSA compared to control subjects. This difference was also ameliorated with CPAP therapy and correlated most strongly with the degree of hypoxemia. The new study by Kobayashi et al4 is important because it suggests the functional involvement of HO in OSA, and provides a basis for CO as a marker of OSA stress. In the current study, CO levels changed within hours of the stress, could be measured easily with a venous blood draw (and possibly could be measured in exhaled breath10), and were affected by treatment. Other biomarkers, such as tumor necrosis factor-α and C-reactive protein, which are thought to reflect the damaging effects of apnea, have been inconsistent in their utility in OSA, as these markers have multiple influences.11 These data suggest several future directions. For the scientist, some questions include: what stress influences CO in OSA patients, and is it repetitive arousal, hypoxemia, or some other factors? Does CO level predict long-term cardiovascular morbidity? Is a low CO level a marker of low cardiovascular risk, or instead is it a reflection of impaired protective responses in a patient who is at increased risk of cardiovascular morbidity? While the HO gene is thought to be relatively conserved, polymorphisms in the promoter region have been associated with variable HO-1 expression and associated with higher risks of cardiopulmonary disease. In the current study, there was wide unexplained variability in CO production among patients with OSA. Are these differences due to promoter polymorphisms or other factors? How should CO be measured (by exhaled breath, serum CO level, or hemoglobin-bound CO)? And when should it be measured (during sleep or on awakening, or do elevations persist for some time)? For clinicians, assuming that the CO level has prognostic value, is it a viable biomarker that should be measured to assess disease burden? Does it reliably reflect the response to treatment? And finally, will exogenous CO one day be a therapy (as has been suggested for other pulmonary diseases) to prevent cardiovascular disease in those with OSA, perhaps in patients nonadherent to CPAP therapy?12 We congratulate Kobayashi et al for fueling the fire on the CO discussion.