Model-based stability assessment of ventilatory control in overweight adolescents with obstructive sleep apnea during NREM sleep.

Obstructive sleep apnea (OSA) involves the interplay of several different factors such as an unfavorable upper airway anatomy, deficiencies in pharyngeal muscle responsiveness, a low arousal threshold, and ventilatory control instability. Although the stability of ventilatory control has been extensively studied in adults, little is known about its characteristics in the pediatric population. In this study, we developed a novel experimental setup that allowed us to perturb the respiratory system during natural non-rapid eye movement (NREM) sleep conditions by manipulating the inspiratory pressure, provided by a bilevel pressure ventilator, to induce sighs after upper airway stabilization. Furthermore, we present a modeling framework that utilizes the noninvasively measured ventilatory responses to the induced sighs and spontaneous breathing data to obtain representations of the processes involved in the chemical regulation of respiration and extract their stability characteristics. After validation with simulated data, the modeling technique was applied to data collected experimentally from 11 OSA and 15 non-OSA overweight adolescents. Statistical analysis of the model-derived stability parameters revealed a significantly higher plant gain and lower controller gain in the OSA group (P = 0.046 and P = 0.007, respectively); however, no differences were found in loop gain (LG) and circulatory time delay between the groups. OSA severity and LG, within the 0.03-0.04-Hz frequency band, were significantly negatively associated (r = -0.434, P = 0.026). Contrary to what has been found in adults, our results suggest that in overweight adolescents, OSA is unlikely to be initiated through ventilatory instability resulting from elevated chemical loop gain.

Development of autonomic dysfunction with intermittent hypoxia in a lean murine model.

Intermittent hypoxia (IH) has been previously shown in a lean murine model to produce sustained hypertension and reverse the diurnal variation of blood glucose (BG). Concomitant glucose infusion attenuated the hypertension but exacerbated the BG fluctuations. In this study, cardiovascular variability analysis was employed to track the development of autonomic dysfunction in mice exposed to room air (IA) or IH, in combination with saline or glucose infusion. Baroreflex sensitivity was found to decrease in all animals, except in the control group. Low-frequency power of pulse interval spectrum, reflecting vagal activity, decreased more rapidly in glucose relative to saline while low-frequency power of blood pressure, reflecting sympathetic activity, decreased more slowly in IH relative to IA. Ultradian (≈ 12 h) rhythmicity was substantially suppressed in IH groups. These findings suggest that IH acted to increase sympathetic activity while glucose infusion led to reduced parasympathetic activity. The combination of IH and hyperglycemia leads to progressively adverse effects on autonomic control independent of obesity.

Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia.

The objective of this study was to non-invasively assess cardiac autonomic control in subjects with sickle cell anemia (SCA) by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxic stimulus. Five African-American SCA patients and seven healthy control subjects were recruited to participate in this study. Each subject was exposed to a controlled hypoxic stimulus consisting of five breaths of nitrogen. Time-varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The confounding effects of changes in respiration on the HRV spectral indices were reduced by using a computational model. A significant decrease in the parameters related to parasympathetic control was detected in the post-hypoxic responses of the SCA subjects relative to normal controls. The spectral index related to sympathetic activity, on the other hand, showed a tendency to increase the following hypoxic stimulation, but the change was not significant. This study suggests that there is some degree of cardiovascular autonomic dysfunction in SCA that is revealed by the response to transient hypoxia.

The effects on cardiovascular autonomic control of repetitive arousal from sleep.

STUDY OBJECTIVES: To quantitatively assess autonomic cardiovascular control in normal young adults following exposure to repetitive acoustically-induced arousals from sleep. DESIGN: Respiration, R-R interval (RRI) and noninvasive measurements of continuous arterial blood pressure were monitored in subjects during the transition from relaxed wakefulness to stable Stage 2 sleep. These measurements were made under undisturbed conditions or conditions in which transient arousals were induced repetitively by acoustic stimulation. A mathematical model was used to partition the fluctuations in RRI into a component ("RSA") correlated with respiration and a component ("A representing baroreflex control of heart rate. The magnitudes and forms of each component before and after exposure to repetitive arousals were compared SETTING: Sleep disorders laboratory in a university setting. PATIENTS OR PARTICIPANTS: Ten healthy young adults (5 male, 5 female) with an average age of 20.4 +/- 2.0 y and mean body-mass index of 23.8 +/- 2.9 kg/m2. INTERVENTIONS: Each subject participated in multiple sleep studies consisting of 4 conditions with 2 nights in each condition. The first condition consisted of undisturbed sleep (control), while in the other 3 conditions, the subjects were aroused from sleep by repetitive auditory stimuli applied continuously over a duration of 50 minutes, with periodicities of 30 seconds, 1 minute, and 2 minutes of sleep. MEASUREMENTS AND RESULTS: Exposure to repetitive arousal (RA) did not alter mean heart rate or blood pressure. However, ABR and RSA gains estimated using the model, increased from the onset of Stage 1 sleep to the start of stable Stage 2 sleep under the control condition, but remained unchanged in all RA conditions. There were also significant increases in low-frequency oscillations of systolic blood pressure in the RA conditions versus no change in the control condition. CONCLUSIONS: Exposure to RA over durations approximating an hour produces cumulative effects on autonomic control that are subtle and can only be detected when advanced signal processing methods are employed. More specifically, the increases in ABR and RSA gains that accompany increasing sleep depth in normal sleep are prevented from occurring.

Determinants of heart rate variability in obstructive sleep apnea syndrome during wakefulness and sleep.

Heart rate variability (HRV) is mediated by at least three primary mechanisms: 1) vagal feedback from pulmonary stretch receptors (PSR), 2) central medullary coupling between respiratory and cardiovagal neurons (RCC), and 3) arterial baroreflex (ABR)-induced fluctuations. We employed a noninvasive experimental protocol in conjunction with a minimal model to determine how these sources of HRV are altered in obstructive sleep apnea syndrome (OSAS). Respiration, heart rate, and blood pressure were monitored in eight normal subjects and nine untreated OSAS patients in relaxed wakefulness and stage 2 and rapid eye movement sleep. A computer-controlled ventilator delivered inspiratory pressures that varied randomly from breath to breath. Application of the model to the corresponding subject responses allowed the delineation of the three components of HRV. In all states, RCC gain was lower in OSAS patients than in normal subjects (P < 0.04). ABR gain was also reduced in OSAS patients (P < 0.03). RCC and ABR gains increased from wakefulness to sleep (P < 0.04). However, there was no difference in PSR gain between subject groups or across states. The findings of this study suggest that the adverse autonomic effects of OSAS include impairment of baroreflex gain and central respiratory-cardiovascular coupling, but the component of respiratory sinus arrhythmia that is mediated by lung vagal feedback remains intact.

Cardiac autonomic function in older adults with sleep-disordered breathing.

We searched for possible associations between various measures of severity of sleep-disordered breathing (SDB) and indices of cardiac autonomic function in older subjects (>60 years). Twenty four overnight unattended homebased based polysomnograms obtained from the Sleep Heart Health Study were analyzed using spectral analysis. For each subject, six autonomic indices reflecting heart rate variability were quantitatively determined during wakefulness, REM sleep and non-REM sleep. Each individual autonomic marker was regressed against each of 4 measures of SDB, including the respiratory disturbance index (RDI), respiratory oscillation index, cumulative oxygen desaturation, and arousal index. In general, we found no correlation between any of these measures of SDB severity and each of the autonomic indices. However, mean heart rate was found to decrease as RDI increased. As well, the ratio of low-frequency to high-frequency power (LHR) decreased with increasing RDI. Contrary to previous reports, our preliminary findings suggest that sympathetic activity decreases with increasing severity of SDB. This paradoxical association between SDB and cardiac autonomic function may be the result of natural compensatory mechanisms at work, allowing some subjects with SDB to be protected from systemic hypertension or other cardiovascular diseases. Supported in part by NIH Grants HL076375, EB001978, HL63463 and HL53941.

Noninvasive assessment of cardiovascular autonomic control in congenital central hypoventilation syndrome.

The goal of this study was to quantify autonomic system dysfunction, as manifested by cardiovascular and respiratory response abnormalities, in patients with congenital central hypoventilation syndrome (CCHS). During wakefulness, we continuously measured the ECG, arterial blood pressure (ABP), airflow, end-tidal CO2 partial pressure (PETCO2), and arterial oxygen saturation (SatO2) in each subject. These measurements were made during spontaneous breathing in supine, sitting and standing postures, and also when each subject tracked his/her prior spontaneous breathing pattern while supine. We also performed the cold face test, hyperoxic hypercapnic rebreathing and the isocapnic hypoxic rebreathing challenges. Using spectral analysis and modeling techniques, we sought to computationally delineate the physiological mechanisms that mediate these abnormalities, as well as to determine the extent to which these abnormalities are related to peripheral or central chemoreflex dysfunction. Our preliminary results support the notion that sympathetic tone is markedly elevated in CCHS, and that differences in autonomic control from normal controls can be delineated by observing the responses to different stressors.

The effects of repetitive arousal from sleep on cardiovascular autonomic control.

A previous study found that the sympathoexcitatory cardiovascular effects of arousal are relatively long lasting. In this study, we examine (1) whether the cumulative effects of arousal can lead to significant changes in autonomic control and (2) how the frequency of arousals affect the magnitude of these effects. Ten healthy subjects were aroused from sleep every 30 seconds, 1 minute and 2 minutes of sleep for an hour. EEG, ABP, ECG and respiration were recorded, and the impulse responses of respiratory sinus arrhythmia (h(RSA)) and arterial baroreflex (h(RSA)) before and after 50 minutes of repetitive arousal were quantified by using a minimal closed loop cardiovascular model. We found that the low frequency baroreflex gain decreased after exposure to repetitive arousals of 2 minutes periodicity but remained unchanged in the control and other arousal conditions.