Effect of weight gain on cardiac autonomic control during wakefulness and sleep

Obesity has been associated with increased cardiac sympathetic activation during wakefulness, but the effect on sleep-related sympathetic modulation is not known. The aim of this study was to investigate the effect of fat gain on cardiac autonomic control during wakefulness and sleep in humans. We performed a randomized, controlled study to assess the effects of fat gain on heart rate variability. We recruited 36 healthy volunteers, who were randomized to either a standardized diet to gain ≈4 kg over 8 weeks followed by an 8-week weight loss period (n=20) or to serve as a weight-maintainer control (n=16). An overnight polysomnogram with power spectral analysis of heart rate variability was performed at baseline, after weight gain, and after weight loss to determine the ratio of low-frequency to high-frequency power and to examine the relationship between changes in heart rate variability and changes in insulin, leptin, and adiponectin levels. Mean weight gain was 3.9 kg in the fat gain group versus 0.1 kg in the maintainer group. Low frequency/high frequency increased both during wakefulness and sleep after fat gain and returned to baseline after fat loss in the fat gain group and did not change in the control group. Insulin, leptin, and adiponectin also increased after fat gain and fell after fat loss, but no clear pattern of changes was seen that correlated consistently with changes in heart rate variability. Short-term fat gain in healthy subjects is associated with increased cardiac sympathetic activation during wakefulness and sleep, but the mechanisms remain unclear.     

Effect of ventilatory drive on upper airway patency in humans during NREM sleep

The pharynx is the site of upper airway obstruction during sleep. As a collapsible tube, pharyngeal patency is determined by transmural pressure and the compliance of the pharyngeal wall. Thus, several factors may influence upper airway patency including the activity of upper airway dilating muscles, the magnitude of caudal traction generated by thoracic inspiratory activity, vascular tone and mucosal surface forces. Changing ventilatory motor output influences upper airway patency primarily by altering dilating muscle activity or caudal traction. Increased ventilatory motor output enhances upper airway patency. Isolated reduction of ventilatory motor output has no significant effect on upper airway patency. However, upper airway narrowing or occlusion occur at the nadir of ventilatory drive during induced periodic breathing and during central apnea. The latter indicates that negative intraluminal pressure is not required for upper airway obstruction during sleep. Therefore, upper airway occlusion during sleep may be due to: (1) passive collapse of a compliant upper airway by gravitational factors or (2) active closure generated by the contraction of the pharyngeal constrictors.     

Effect of CPAP treatment on inspiratory arousal threshold during NREM sleep in OSAS

The maximal inspiratory effort recorded at the end of apnea has been considered as an index of arousal threshold in obstructive sleep apnea syndrome (OSAS). Previous investigations have shown that the arousal threshold is higher in patients with OSAS than in normal subjects. The aim of the present study was to investigate the effect of continuous positive airway pressure (CPAP) treatment on the inspiratory-effort-related arousal threshold in patients with OSAS. In ten male patients, 40 episodes of apnea during stage 2 non-REM (NREM) sleep were analyzed. Apnea duration (t), esophageal pressure (Pes) at the first occluded breath (Pes1), the minimum of the three initial Pes swings (Pes min), the maximum of the three final Pes swings (Pes Max), Pes (Pes Max–Pes min), RPes (rate of increase of intrathoracic pressure, Pes/t), n (number of occluded breaths during apnea), Pes/n, n/t, and SaO₂ were determined before and after occlusion. These apneic episodes were compared to ten episodes of apnea provoked by a mask occlusion device after 1, 7, 30, and 90 days of CPAP treatment. The therapy resulted in a decrease in the inspiratory-effort-related arousal threshold, as measured by a reduction of Pes Max, without significant changes in apnea duration and apnea-related hypoxemia. Pes1 and Pes/n, which are markers of respiratory drive, significantly decreased between observations. CPAP treatment decreases the inspiratory-effort-related arousal threshold and induces a decrease in ventilatory drive in response to upper airway occlusion.     

Arterial oxygen desaturation during sleep in interstitial pulmonary disease. Correlation with chemical control of breathing during wakefulness

Patients with IPD often develop oxygen desaturation during sleep. We investigated whether or not the degree of falls in SaO2 during sleep were correlated with the daytime data of pulmonary function tests, arterial blood gas tensions, or ventilatory responses to chemical stimuli. Fourteen patients with IPD who had restrictive ventilatory impairment were studied to evaluate these relationships. The magnitude of SaO2 depression from awake to REM sleep was inversely correlated with the level of baseline SaO2. Hypercapnic ventilatory response was inversely related to the amount of maximal desaturation in both REM and NREM sleep. These results indicate that patients with IPD who have insufficient ventilatory response to hypercapnia reveal larger falls in SaO2 during sleep, particularly if they have lower baseline SaO2.     

Braking of expiratory airflow in obese pigs during wakefulness and sleep.

Braking of expiratory airflow is a phenomenon prominently seen in neonates where it is thought to defend end-expiratory lung volume. This paper describes pronounced expiratory braking in an adult animal, the obese Vietnamese pot-bellied pig. Three obese pigs were chronically instrumented for recording of intrapleural pressure and bioelectric signals related to sleep. Airflow was measured by a pneumotachograph attached to a facemask. Expiratory airflow resistance was calculated for 10 consecutive expirations during wakefulness, NREM, and REM sleep. All animals demonstrated a biphasic expiratory flow pattern characterized by an initial plateau in flow at a low value followed by a rapid increase later in expiration. Airflow resistance during early expiration was on average four-fold higher than during late expiration. A striking observation was the maintenance of pronounced expiratory braking during NREM and REM sleep. Expiratory braking in these animals is likely due to laryngeal mechanisms and may serve to preserve end-expiratory lung volume or improve hemodynamics.     

Upper airway mechanics and post-hypoxic ventilatory decline during NREM sleep

Termination of hypoxia results in a transient ventilatory decline referred to as post-hypoxic ventilatory decline (PHVD). We wished to determine whether PHVD is due to changes in ventilatory motor output or upper airway mechanics. We studied 19 healthy normal subjects (15 men, 4 women) during stable non-REM (NREM) sleep. Subjects were exposed to multiple episodes of brief (3 min) hypoxia that terminated with one breath of 100% FI_O2. Minute ventilation (V _I), tidal volume (V _T), timing, and upper airway resistance (R _ua) were measured during the control, hypoxia, and for the first six breaths immediately after cessation of hypoxia. In addition, we measured diaphragmatic electromyograms (EMGdia) via surface electrodes in four subjects. V _I and V _T decreased during the recovery period to a nadir of 81and 83% of room air control, respectively. However, there was no significant change in respiratory frequency or upper airway resistance during the post-hypoxic recovery period. Decreased V _I was associated with a comparable decrease in EMGdia. We conclude that: (1) PHVD occurs in normal humans during NREM sleep, (2) there is no evidence of post-hypoxic frequency decline in humans during NREM sleep, and (3) PHVD is centrally mediated and not driven by upper airway mechanics.     

Hyperinflation and expiratory muscle recruitment during NREM sleep in humans

The purpose of this study was to determine the effect of hyperinflation on expiratory muscle recruitment during NREM sleep in healthy humans. Hyperinflation was produced by negative pressure in a tank ventilator or application of positive end-expiratory pressure (PEEP). Expiratory and inspiratory electromyograms (EMGexp and EMGinsp) were measured using transcutaneously implanted wire and surface electrodes, respectively. During wakefulness, sustained hyperinflation (3-5 min, +0.72 +/- 0.31 L) in the tank respirator caused augmentation of EMGexp (+77%, P less than 0.05) and EMGinsp (+27%, P less than 0.05) in all subjects. Brief hyperinflation with PEEP (5 breaths, +0.53 +/- 0.32 L) augmented EMGexp in 3 of 6 subjects and EMGinsp in 5 of 5 subjects (+98%, P less than 0.05). During NREM sleep, sustained hyperinflation (+0.54 +/- 0.17 L) in the tank respirator caused no change in EMGexp and a small increase in EMGinsp (+9%, P less than 0.001). Brief hyperinflation with PEEP (0.29 +/- 0.10 L) caused no change in EMGexp or EMGinsp. Sustained hyperinflation with PEEP activated EMGexp only in subjects whose end-tidal CO2 increased. We concluded that moderate hyperinflation does not recruit expiratory muscles during NREM sleep as it does during wakefulness.     

Breathing during wakefulness and sleep after human heart-lung transplantation

To study the effects of pulmonary denervation on breathing during sleep, sleep studies were conducted on seven heart-lung transplant recipients (H-LT) and a comparable number of sex-matched normal subjects of similar age. Four of the H-LT patients had a restrictive pattern on spirometry. The time since transplantation ranged from 45 to 1,102 days. There were no significant differences between the groups with respect to total sleep time or distribution of sleep stages. There were no significant differences between the H-LT recipients and normal subjects with respect to baseline awake oxyhemoglobin saturation (SaO2) or the nadirs of SaO2 during REM and non-REM sleep, the absolute number and frequency (number per hour of sleep) of apneas, hypopneas, desaturation events, both over the whole night of study or separately during non-REM and REM sleep. Across wakefulness and all sleep stages, the H-LT patients tended to have shorter total respiratory cycle times (Ttot) (p = 0.052) and more rapid breathing frequency (F) than the normal subjects. This was associated with significantly shorter inspiratory times (Tl) (p less than 0.001) and smaller duty cycles (Tl/Ttot) (p less than 0.005) in the H-LT recipients. During non-REM and REM sleep, F tended to be higher in the H-LT recipients with pulmonary restriction than in the nonrestricted patients. There were no significant differences between the H-LT recipients and the normal subjects with regard to the periodicity of breathing, either in terms of timing parameters or breath amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)     

Accuracy of respiratory inductive plethysmography during wakefulness and sleep in patients with obstructive sleep apnea.

To assess the accuracy of the respiratory inductive plethysmograph (RIP) during sleep in obese patients with obstructive sleep apnea (OSA), we monitored 13 patients with OSA during wakefulness and nocturnal sleep with simultaneous measurements of tidal volume from RIP and integrated airflow. Patients wore a tightly fitting face mask with pneumotachograph during wakefulness and sleep. Calibrations were performed during wakefulness prior to sleep and compared with subsequent wakeful calibrations at the end of the study. Patients maintained the same posture during sleep (supine, 11; lateral, two) as during calibrations. There were no significant differences in calibrations before sleep and after awakening. The mean error in 13 patients undergoing RIP measurements of tidal volume during wakefulness was -0.7 +/- 3.4 percent while that during sleep was 2.1 +/- 14.9 percent (p < 0.001). The standard deviation (SD) of the differences between individual breaths measured by RIP and integrated airflow was 9.8 +/- 5.5 percent during wakefulness and 25.5 +/- 18.6 percent during sleep (p < 0.001). During both wakefulness and sleep, errors in RIP tidal volume were not significantly correlated with body mass index. In 12 patients with at least 10 percent time in each of stages 1 and 2 sleep, SD was greater in stage 2 sleep compared with wakefulness and stage 1 (p < 0.001). In three patients who manifested all stages of sleep, SD was greater in REM sleep than in wakefulness and all stages of non-REM sleep (p < 0.001). In three patients who manifested all stages of sleep, SD was greater in REM sleep than in wakefulness and all stages of non REM sleep (p < 0.001). This was associated with paradoxic motion of the rib cage in two patients during REM. We conclude that, despite increased errors in individual breath measurements during sleep, more marked during stages 2 and REM sleep, RIP is clinically useful to measure ventilation quantitatively in obese patients with sleep apnea. The criterion of a decrease of 50 percent in tidal volume assessed by RIP is appropriate to define hypopneas in such patients.     

The effects of transcutaneous electrical stimulation during wakefulness and sleep in patients with obstructive sleep apnea.

Upper airway (UA) collapse in obstructive sleep apnea (OSA) is considered in part to result from the decrease in UA dilator muscle tone that occurs during sleep. We hypothesized that augmentation of UA muscle function by transcutaneous electrical stimulation (TES) might function to enlarge UA size during wakefulness and/or prevent UA collapse during sleep in patients with OSA. Eight male patients with OSA were studied both awake and asleep, with TES administered to the submental region in two patients and to both the submental and subhyoid regions in six patients. Fast-CT scans obtained at FRC and end-inspiration (VTei) demonstrated increased UA size with tidal breathing, p less than or equal to 0.05. The active generation of -10 cm H2O pressure at FRC substantially decreased UA size, p less than or equal to 0.001. However, no changes in UA size were detected at either FRC or VTei with TES applied at 50 and 100% of the maximal tolerated intensity. The collapsibility of the UA in response to the generation of -10 cm H2O pressure was also unchanged by TES. In contrast to the lack of effect of TES on UA size, voluntary protrusion of the tongue increased cross-sectional area (CSA) of the orohypopharyngeal (OHP) segment of the UA, p less than 0.05, and to a lesser extent the CSA of the distal velopharyngeal segment, p = 0.06. When applied during sleep, TES failed to prevent or improve either sleep-disordered breathing or sleep architecture.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sublingual electrical stimulation of the tongue during wakefulness and sleep

Pharyngeal obstruction in patients with obstructive sleep apnea (OSA) is thought to result from decreased upper airway muscle tone during sleep. The goal of the present study was to estimate the role of the tongue muscles in maintaining pharyngeal patency during sleep. Using non-invasive, sub-lingual surface electrical stimulation (ES), we measured tongue protrusion force during wakefulness and upper airway resistance during sleep in seven healthy subjects and six patients with OSA. During wakefulness, ES produced similar protrusion forces in healthy subjects and patients with OSA. ES of the anterior sublingual surface, causing preferential contraction of the genioglossus, resulted in smaller effects than combined ES of the anterior and lateral surface, which also stimulated tongue retractors. During sleep, trans-pharyngeal resistance decreased and peak inspiratory flow rate increased from 319+/-24 to 459+/-27 and from 58+/-16 to 270+/-35 ml/sec for healthy subjects and OSA patients, respectively (P<0.001). However, ES was usually unsuccessful in reopening the upper airway in the presence of complete apneas. We conclude that non-invasive ES of the tongue improves flow dynamics during sleep. Combined activation of tongue protrusors and retractors may have a beneficial mechanical effect. The magnitude of responses observed suggests that in addition to the stimulated muscles, other muscles and/or forces have a substantial impact on pharyngeal patency.     

Computerized tomography in obstructive sleep apnea. Correlation of airway size with physiology during sleep and wakefulness

Pathophysiologic changes during sleep in patients with obstructive apnea are often associated with alterations in upper airway function during awake periods. To determine whether these functional changes are related to abnormal airway structure, we performed computerized tomography (CT) in 20 awake patients with obstructive apnea and in 10 control subjects. The CT scan measurements of cross-sectional areas of the nasopharynx, oropharynx, and hypopharynx in apneic patients were significantly reduced (p less than 0.05) compared with those in the control subjects. Sites of obstruction varied, and apparent airway occlusion occurred in 6 patients. Reduced pharyngeal size correlated with increased sleep-disordered breathing rates (p less than 0.05), more severe nocturnal oxygen desaturation (p less than 0.05), and the presence of a saw-tooth pattern of flow-volume curves obtained during awake periods (p less than 0.05). Structural upper airway narrowing is detectable with CT in awake patients with obstructive sleep apnea.     

Genioglossus activity in children with obstructive sleep apnea during wakefulness and sleep onset

A prominent role for upper airway neuromuscular control mechanisms in the pathophysiology of pediatric obstructive sleep apnea syndrome (OSAS) is suggested by the observation that obstruction does not occur during wakefulness and is infrequently seen during non-REM sleep. Using a custom intraoral surface electrode to record genioglossal activity (genioglossal electromyography [EMGgg]), normalized with a maximal maneuver, we studied 10 children with OSAS and 6 normal control subjects to determine EMGgg activity during (1) wakefulness, (2) the sleep onset period, and (3) stable non-REM sleep. We observed that the EMGgg activity in patients with OSAS compared with control subjects was significantly greater during wakefulness (3.6 +/- 1.8 vs. 1.6 +/- 1.8% maximum, p < 0.05) and had a greater decline during the early and late sleep onset period (p < 0.05). During stable non-REM sleep, EMGgg remained below the wakeful baseline in all normal control subjects but increased above the baseline in four of the patients with OSAS. We speculate that the increased EMGgg activity during wakefulness represents a reflex-driven neuromuscular compensation for an anatomically compromised airway. Furthermore, the larger decline in EMGgg at sleep onset observed in patients with OSAS is consistent with the relative loss of this reflex. Finally, the return of EMGgg activity above baseline in patients with severe OSAS suggests that some chemical or mechanical compensatory mechanisms remain active during stable non-REM sleep in children.     

Neurophysiology of sleep and wakefulness

Wakefulness, NREM sleep, and REM sleep are three distinct states of existence. Each state has characteristic behavioral and physiologic patterns,and each has specific neurophysiologic mechanisms associated with its generation and control. Structures in the brainstem use various neurotransmitters to influence higher brain structures in the midbrain and cortex. The ARAS provides cholinergic, noradrenergic, and glutaminergic stimulation to the thalamus, hypothalamus, and basal forebrain resulting in cholinergic and glutaminergic excitation of the cortex. An active cortex that exhibits a characteristic pattern of desynchronized EEG manifests wakefulness. Various factors affect the need and timing of sleep onset. These factors influence the nucleus tractus solitarius, causing its noradrenergic projections to midbrain and forebrain structures to inhibit activity in the ARAS, resulting inactivation of inhibitory GABAergic thalamocortical projections to the cor-tex. During a state of decreased activation, the cortex exhibits a pattern of synchronized EEG. Transition between NREM sleep and REM sleep is controlled by noradrenergic neurons in the loci coeruleus and serotoninergic neurons in the raphe called REM-off cells and cholinergic neurons in the nucleus reticularis pontis oralis called REM-on cells. Other brain structures are involved in generation and control of REM sleep-related phenomena, such as eye movement and muscle atonia. During wakefulness, there is increased sympathetic tone and decreased parasympathetic tone that maintains most organ systems in a state of action or readiness. During NREM sleep, there is decreased sympathetic tone and increased parasympathetic activity that creates a state of reduced activity. REM sleep is characterized by increased parasympathetic activity and variable sympathetic activity associated with increased activation of certain brain functions. The states of wakefulness and sleep are characterized as stages that are defined by stereotypical EEG, EMG, and EOG patterns. Wakefulness stage has an EEG pattern predominated by the alpha rhythm. With onset of stage 1 sleep, the alpha rhythm attenuates, and an EEG pattern of relatively low voltage and mixed frequency is seen. Progression to stage 2 sleep is defined by the appearance of sleep spindles or K-complexes. Further progression into the deepest sleep stages 3 and 4 is defined by the occurrence of high-amplitude, low-frequency EEG activity. The progression of sleep stages occurs in cycles of 60 to 120 minutes throughout the sleep period. Various circadian environmental and ontologic factors affect the pattern of sleep stage occurrence.     

Respiratory function during wakefulness and sleep among survivors of respiratory and non-respiratory poliomyelitis.

The purpose of this study was to determine whether there is a difference in respiratory mechanics and gas exchange between polio survivors and healthy, age-matched controls during wakefulness and sleep. Polio survivors were divided into four groups. The first group included those who had evidence of respiratory muscle involvement originally (PRM) and the second group included those who had bulbar muscle involvement originally (PBM). The third and fourth groups had only limb involvement originally but were separated by absence (PSL) or presence of a scoliosis (PSS) at the time of their evaluation. Each subject completed baseline and one year follow-up measurements of lung volumes, diffusion, flow rates, respiratory muscle strength, central and peripheral chemoreflexes and arterial blood gases. Sleep measurements included a full respiratory polysomnographic study. Fifty polio survivors and 13 controls completed the study. The PRM and PSS groups had an elevated arterial carbon dioxide tension (PaCO2) (mean +/- SE 6.0 +/- 0.4 and 6.0 +/- 0.3 kPa, respectively), reduced vital capacity (2.8 +/- 0.3 and 2.9 +/- 0.3 l, respectively), reduced maximal inspiratory pressure (-5.9 +/- 0.7 and -5.4 +/- 0.8 kPa, respectively) and reduced maximal expiratory pressure (9.8 +/- 1.1 and 9.1 +/- 1.2 kPa, respectively), when compared with non-polio controls. During sleep PRM and PSS groups experienced a higher PaCO2 (6.5 +/- 0.5 and 6.7 +/- 0.4 kPa, respectively) and a lower arterial oxygen saturation (SaO2) (89 +/- 4 and 86 +/- 3%, respectively). There were no differences among groups for diffusion, flow rates and chemoreflexes. All other polio survivors showed essentially normal respiratory function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoxemia and hypercapnia during exercise and sleep in patients with cystic fibrosis.

BACKGROUND: In patients with cystic fibrosis (CF), it has been proposed that hypoxemia and hypercapnia occur during episodes of stress, such as exercise and sleep, and that respiratory muscle weakness because of malnutrition may be responsible. METHODS: Pulmonary function, respiratory muscle strength, and nutrition were assessed and correlated with the degree of hypoxemia and hypercapnia during exercise and sleep in 14 patients with CF and 8 control subjects. RESULTS: Despite no differences in maximum static inspiratory pressure (PImax) between the two groups, the CF group developed more severe hypoxemia (minimum oxyhemoglobin saturation [SpO2], 89 +/- 5% vs 96 +/- 2%; p < 0.001) and hypercapnia (maximum transcutaneous CO2 tension [PtcCO2], 43 +/- 6 vs 33 +/- 7 mm Hg; p < 0.01) during exercise. Similarly, during sleep, the CF group developed greater hypoxemia (minimum SpO2, 82 +/- 8% vs 91 +/- 2%; p < 0.005), although CO2 levels were not significantly different (maximum PtcCO2, 48 +/- 7 vs 50 +/- 2 mm Hg). Within the CF group, exercise-related hypoxemia and hypercapnia did not correlate with FEV1, residual volume/total lung capacity ratio (RV/TLC), PImax, or body mass index (BMI). Hypoxemia and hypercapnia during sleep correlated with markers of gas trapping (RV vs minimum arterial oxygen saturation [r = -0.654; p < 0.05]), RV vs maximum PtcCO2 (r = 0.878; p < 0.001), and RV/TLC vs maximum PtcCO2 (r = 0.790; p < 0.01) but not with PImax or BMI. CONCLUSION: Patients with moderately severe CF develop hypoxemia and hypercapnia during exercise and sleep to a greater extent than healthy subjects with similar respiratory muscle strength and nutritional status. Neither respiratory muscle weakness nor malnutrition are necessary to develop hypoxemia or hypercapnia during exercise or sleep.     

Central chemosensitivity, sleep, and wakefulness.

Neurons in many regions of the lower brain are chemosensitive in vitro. Focal acidification of these same and other regions in vivo can stimulate breathing indicating the presence of chemoreception. Why are there so many sites for central chemoreception? This review evaluates data obtained from unanesthetized rats at three central chemoreceptor sites, the retrotrapezoid nucleus (RTN), the medullary raphé, and the nucleus tractus solitarius (NTS) and extends ideas concerning two hypotheses, which were recently formulated (Nattie, E., 2000. Respir. Physiol. 122, 223-235). (1) The high overall sensitivity of the respiratory control system in the unanesthetized state to small increases in arterial CO(2) relies on an additive or greater effect of these multiple chemoreceptor sites. (2) Chemoreceptor sites can vary in effectiveness dependent on the state of arousal. These ideas fit into a more speculative and general hypothesis that central chemoreceptors are organized in a hierarchical manner as proposed for temperature sensing and thermoregulation (Satinoff, E., 1978. Science 201, 16-22). The presence of a number of chemosensitive sites with varying thresholds, sensitivity, and arousal dependence provides finely tuned control and stability for breathing.     

Abnormal breathing during sleep and chemical control of breathing during wakefulness in patients with sleep apnea syndrome

The possible role of ventilatory control in relation to sleep apnea has not yet been clarified. We investigated the relationship between awake ventilatory drives to hypoxia and hypercapnia and sleep-disordered breathing in 21 subjects with sleep apnea syndrome. The awake hypoxic ventilatory drive, which was evaluated by occlusion pressure responses, was inversely correlated with the magnitude of maximal oxygen desaturation during sleep as well as the ratio of duration with more than 4 and 10% oxygen desaturation to total sleep time. On the other hand, the awake hypercapnic ventilatory drive was not correlated with these parameters of sleep desaturation. Apnea index and duration were not correlated with the degree of hypoxic or hypercapnic ventilatory drive, respectively. Our study concluded that sleep desaturation is better correlated with hypoxic ventilatory drive than with hypercapnic ventilatory drive in patients with sleep apnea syndrome. These results are different from the results obtained in the patients with COPD in our previous study.