Hypocapnia is associated with increased upper airway expiratory resistance during sleep

We hypothesized that hypocapnia is responsible for increased expiratory resistance during NREM sleep. Hypocapnia was induced by hypoxic hyperventilation in 21 subjects (aged 29.4 ± 7.8 yrs, 10 women, BMI 24.4 ± 4.3 kg/m(2)). Isocapnic hypoxia was induced in 12 subjects of whom, 6 underwent hypocapnic hypoxia in the same night. Upper airway resistance (R(UA)) was measured at the linear pressure-flow relationship during inspiration and expiration. Inspiratory flow limitation (IFL) was defined as the dissociation in pressure-flow relationship. (1) Expiratory R(UA) increased during hypocapnic but not isocapnic hypoxia relative to control (11.0 ± 5.6 vs. 8.2 ± 3.6 cm H(2)O/L/s; p < 0.05, and 11.45.0 vs. 10.94.4 cm H(2)O/L/s; p = NS, respectively). (2) No gender difference was found in R(UA) (p = NS). (3) Increased expiratory R(UA) correlated with the IFL change during hypocapnic but not isocapnic hypoxia. (4) No changes were noted in inspiratory R(UA) or IFL. Expiratory R(UA) increased during hypocapnia and was associated with IFL, indicating upper airway narrowing. Gender does not influence the upper airway response to hypocapnic hypoxia.     

The time structure of the cyclic alternating pattern during sleep

STUDY OBJECTIVES: To analyze the intervals between A phases of the cyclic alternating pattern (CAP) and to describe their time structure. This might represent an additional aspect to be studied in sleep pathologies that are accompanied by CAP changes. METHODS: Sleep stages and CAP A phases were identified in polysomnographic night recordings of normal adults and children. Intervals between consecutive CAP A phases were measured, counted, and used to draw individual normalized distribution graphs. The intervals during light sleep (stages 1 and 2) were analyzed separately from those occurring during slow-wave sleep (SWS). Subsequently, we performed a Markovian analysis of intervals, in order to describe in detail their time structure. SETTING: N/A. PARTICIPANTS: Twenty-four adults and 28 children. MEASUREMENTS AND RESULTS: In adults, a preponderance of intervals shorter than 60 seconds during SWS was found; light sleep showed a higher number of intervals longer than 60 seconds. A less clear-cut difference between stages was found in children, who showed a shift of the peak in their SWS histogram toward intervals shorter than in adults. Interval sequences were not determined by a random process in both groups. The Markovian analysis showed statistically significant lower values of entropy and higher values of time dependency, mostly in adults during SWS. CONCLUSIONS: The different CAP components of sleep occur in a non-random ordered fashion, and their time structure is characterized by first-order relationships. SIGNIFICANCE: We postulate that CAP components are the expression of a timely ordered process that exhibits specific sleep stage-related features and undergoes age-related modifications.     

Borderline intellectual functioning and sleep: The role of cyclic alternating pattern

In the clinical literature there are few specific studies about the relationship between cognition processes and sleep during childhood. In addition, milder deficits in general intellectual capacity have received less attention relative to major cognitive dysfunctions (such as the genetic or environmental basis of mental retardation), especially concerning the low normal and borderline status. Sleep could play a key role in multiple intellectual abilities such as memory, executive functions, and school performances. Aim of our study is to assess the sleep macrostructure and NREM instability (cyclic alternating pattern) and their relationship with IQ in a sample of subjects with borderline intellectual functioning (BIF). The DSM-IV defines BIF as a total intelligence quotient (TIQ) ranging between 71 and 84. Intellective functioning was assessed using the Italian version of Wechsler Intelligence Scale for Children-Revised (WISC-R), a well validated test for the developmental age between 6 and 16. For this study, 12 BIF and 17 healthy children, matched for sex and age, underwent an overnight PSG recording. Macrostructural sleep and CAP analysis were also performed. To our knowledge, this study represents the first attempt to evaluate sleep architecture and NREM instability organization in children with BIF. Findings from this investigation evidence that BIF presents alterations in both macro- and microstructural sleep architecture, with an interesting statistical significant correlation with IQ.     

The cyclic alternating pattern as a physiologic component of normal NREM sleep

The cyclic alternating pattern (CAP) is a long-lasting periodic activity consisting of two alternate electroencephalogram (EEG) patterns. This variation in EEG is closely related to fluctuations in the level of arousal that characterize two different functional states in the arousal control mechanism. We studied 20 sleep records of 10 healthy subjects to see if CAP appears under physiologic conditions. During NREM sleep, CAP corresponded to a periodic succession of spontaneous phasic phenomena recurring within every stage, i.e., intermittent alpha rhythm, K-complex sequences, and reactive slow wave sequences. The following analyses were performed. Each EEG specific alternating pattern, defined as a cycle, was subdivided into two phases depending on the arousal response to stimulation. Average cycle length, average duration of each phase, and average ratio phase/cycle were calculated. CAP rate defined as (CAP time/Sleep time) was calculated for total sleep time (TST), (Cap time/TST); for NREM sleep, (CAP time/Total NREM); and for each NREM sleep stage. CAP is the EEG translation of the reorganization of the sleeping brain challenged by the modification of environmental conditions.     

Changes in upper airway resistance during progressive normocapnic hypoxia in patients with obstructive sleep apnoea syndrome

SUMMARY  The responses of the upper airway to progressive normocapnic hypoxia were studied in 6 healthy men and in 6 patients with obstructive sleep apnoea syndrome (OSAS). The upper airway resistance was calculated by the ratio of the laryngeal pressure (measured using a catheter introduced into oesophagus) to the inspiratory flow. Additionally, genioglossal EMG activity (GG-EMG) was measured and analysed. The changes of all variables were analysed individually for each subject. The OSAS patients showed reduced ventilatory response, GG-reactivity and changes in upper airway resistance during progressive hypoxia. It is concluded that impaired reactivity to hypoxic activation (probably due to the process of adaptation of carotid chemoreceptors to nocturnal hypoxia), might reduce the defence abilities of OSAS patients against episodes of obturation in upper airway and obstructive apnoea events.     

Changes in upper airway resistance during progressive normocapnic hypoxia in patients with obstructive sleep apnoea syndrome

The responses of the upper airway to progressive normocapnic hypoxia were studied in 6 healthy men and in 6 patients with obstructive sleep apnoea syndrome (OSAS). The upper airway resistance was calculated by the ratio of the laryngeal pressure (measured using a catheter introduced into oesophagus) to the inspiratory flow. Additionally, genioglossal EMG activity (GG-EMG) was measured and analysed. The changes of all variables were analysed individually for each subject. The OSAS patients showed reduced ventilatory response, GG-reactivity and changes in upper airway resistance during progressive hypoxia. It is concluded that impaired reactivity to hypoxic activation (probably due to the process of adaptation of carotid chemoreceptors to nocturnal hypoxia), might reduce the defence abilities of OSAS patients against episodes of obturation in upper airway and obstructive apnoea events.     

Microstructure of sleep in depressed patients according to the cyclic alternating pattern

BACKGROUND: The aim of this study was to evaluate the microstructure of the EEG sleep of depressed subjects by cyclic alternating pattern (CAP) analysis. METHODS: 78 patients affected by major depression and 18 control subjects matched for age and sex underwent a full night polysomnographic study. RESULTS: A significant increase in CAP rate (60 versus 35%) was found in the patients group compared to controls while no significant difference was found with the traditional analysis. CONCLUSION: In depressed subjects CAP analysis is able to show a microstructural sleep impairment, which is not evident at the macrostructural level, providing an objective measure of sleep disturbance in those patients.     

Sleepiness and residual sleepiness in adults with obstructive sleep apnea

Sleepiness is a common, but not necessary symptom of the obstructive sleep apnea syndrome (OSA) and is a frequent chief complaint of patients with OSA who seek medical attention. While sleepiness may seem simple in nature, the underlying mechanisms producing daytime sleepiness in OSA are complex and poorly characterized. Moreover, the meaningful assessment of pathological sleepiness is frequently far from straightforward. Effective treatment of OSA is generally expected to resolve or ameliorate daytime sleepiness. An unknown percentage of treated OSA patients, however, remain sleepy during waking hours. The assessment and treatment of residual sleepiness in treated OSA can range from simple to difficult, depending on the nature and causes of the continued sleepiness. Recently, however, data from clinical trials have been generated which provide direction in the evaluation and management of the OSA patient suffering residual daytime sleepiness.     

Alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by gaboxadol and zolpidem

Objective:

To evaluate cyclic alternating pattern (CAP) in a phase advance model of transient insomnia and the effects of gaboxadol and zolpidem.

Design:

A randomized, double-blind, cross-over study in which habitual sleep time was advanced by 4 h.

Setting:

6 sleep research laboratories in US

Participants:

55 healthy subjects (18-57 y)

Interventions:

Gaboxadol 15 mg (GBX), zolpidem 10 mg (ZOL), and placebo (PBO).

Measurements:

Routine polysomnographic (PSG) measures, CAP, spectral power density, and self-reported sleep measures

Results:

The phase advance model of transient insomnia produced significant changes in CAP parameters. Both GBX and ZOL significantly and differentially modified CAP parameters in the direction of more stable sleep. GBX brought the CAP rate in stage 1 sleep and slow wave sleep (SWS) closer to baseline levels but did not significantly change the CAP rate in stage 2. ZOL reduced the CAP rate in stage 2 to near baseline levels, whereas the CAP rate in stage 1 and SWS was reduced substantially below baseline levels. The CAP parameter A1 index (associated with SWS and sleep continuity) showed the highest correlation with self-reported sleep quality, higher than any traditional PSG, spectral, or other self-reported measures.

Conclusion:

Disruptions in CAP produced by phase advanced sleep were significantly and differentially modulated by gaboxadol and zolpidem. The relative independence of CAP parameters from other electrophysiological measures of sleep, their high sensitivity to sleep disruption, and their strong association with subjective sleep quality suggest that CAP variables may serve as valuable endpoints in future insomnia research.

Citation:

Svetnik V; Ferri R; Ray S; Ma J; Walsh JK; Snyder E; Ebert B; Deacon S. Alterations in cyclic alternating pattern associated with phase advanced sleep are differentially modulated by gaboxadol and zolpidem. SLEEP 2010;33(11):1562-1570.     

Non-linear EEG measures during sleep: effects of the different sleep stages and cyclic alternating pattern.

The objective of this work was to study the non-linear aspects of sleep EEG, taking into account the different sleep stages and the peculiar organization of its phasic events in ordered sequences (CAP) by applying a series of new non-linear measures (non-linear cross prediction or NLCP), which appear more reliable for the detection and characterization of non-linear structures in experimental data than the commonly used correlation dimension. Eight healthy subjects aged 18-20 years participated in this study. Polysomnography was performed in all subjects; signals were sampled at 128 Hz and stored on hard disk. The C3 or C4 derivation was used for all the subsequent computational steps, which were performed on EEG epochs (4096 data points) selected from sleep stage 2 (S2) and slow-wave sleep (SWS), in both CAP and non-CAP (NCAP) conditions. Also, epochs from sleep stage 1 (S1), REM and wakefulness preceding sleep were recorded. The dynamic properties of the EEG were assessed by means of the non-linear cross-prediction test, which uses three different 'model' time series in order to predict non-linearly the original data set (Pred, Ama, and Tir). Pred is a measure of the predictability of the time series, and Ama and Tir are measures of asymmetry, indicating non-linear structure. The non-linear measures applied in this study indicate that sleep EEG tends to show non-linear structure only during CAP periods, both during S2 and SWS. Moreover, during CAP periods, non-linearity can only be detected during the phase A1 subtypes (and partially A2) of CAP. The A3 phases show characteristics of non-stationarity and bear some resemblance to wakefulness. Based on the results of this study, sleep might be considered as a dynamically evolving sequence of different states of the EEG, which we could track by detecting non-linearity, mostly in association with CAP. Our results clearly show that detectable non-linearity in the EEG is closely related to the occurrence of the phase A of CAP.     

The influence of the menstrual cycle on upper airway resistance and breathing during sleep

STUDY OBJECTIVE: Female hormones, specifically progesterone, that peak in the luteal phase may play a significant role in protecting premenopausal women from sleep-disordered breathing. The influence of female hormones on upper airway resistance during sleep was investigated during the follicular and luteal phases of normal menstrual cycles. SETTING: Hospital-based sleep laboratory. DESIGN AND PARTICIPANTS: Healthy women with verified ovulatory cycles and without sleep complaints were recruited into the study. Sleep and upper airway resistance data (mean +/- SD) were collected on 2 nights from 11 women (21-49 years of age [28 +/- 9 years], body mass index of 22.8 +/- 3.6 kg/m2), once during the follicular phase (day 6-11) and once in the luteal phase (day 19-23) in random order. MEASUREMENTS AND RESULTS: Nasal resistance, standardized to a flow rate of 0.3 L/second, measured using posterior active rhinomanometry immediately prior to the sleep study, did not differ between the 2 phases. The respiratory disturbance index tended to be higher in the follicular phase than in the luteal phase and was above 5 per hour for 3 women in the follicular phase. Upper airway resistance, controlled for flow rate and body position, was calculated for 50 random breaths during wakefulness, stage 1, stage 2, slow-wave, and rapid eye movement sleep. During wake and stage 2 sleep, upper airway resistance was significantly higher in the follicular phase than in the luteal phase, as was the overall upper airway resistance combined for wake and across all sleep stages. Combining data from the 2 nights, compared to wake, upper airway resistance increased in stage 2, slow-wave, and rapid eye movement sleep. CONCLUSIONS: Within the menstrual cycle, upper airway resistance is lower in the luteal compared with the follicular phase.     

Evaluation of EEG cyclic alternating pattern during sleep in insomniacs and controls under placebo and acute treatment with zolpidem.

In nonrapid eye movement (NREM) sleep, electroencephalographic cyclic alternating patterns (CAPS) express the organized complexity of arousal-related phasic events. As a translation of sustained instability of the arousal level, CAPS increase under perturbation and decrease under sleep-promoting conditions. After adaptation to the sleep lab, 18 subjects (12 with persistent psychophysiological insomnia and 6 without sleep complaints), all aged 40-60 years, underwent a random sequence of two nonconsecutive nocturnal recordings, one under placebo and one under an imidazopyridine hypnotic agent (zolpidem). The choice of this drug was oriented by its capability to warrant, at the selected dose of 10 mg, a physiological profile of sleep. Polysomnographic parameters and self-report of sleep quality by means of visual analogue scale (VAS) were assessed by analysis of variance followed by a Scheffé test when F statistics were significant. The placebo nights of controls showed a significantly longer duration of total sleep time (+60 minutes) compared with the placebo nights of insomniacs. However, no relevant differences emerged from the other traditional polysomnographic variables. Conversely, CAP rate (CAP time x 100/NREM sleep time) showed highly sensitive and consistent modifications. Under placebo, CAP rate was significantly higher among insomniacs compared with controls (62.2% vs. 38.5%). Under medication, CAP rate dropped to 26.8% in insomniacs, whereas it was only moderately reduced in controls (31%). CAP rate values paralleled the self-rating estimation of sleep quality, but the VAS means differed significantly only among insomniacs where a sharp average fall from 45 mm (placebo nights) to 15 mm (zolpidem nights) could be detected. Our findings suggest that CAP rate in sleep analysis can represent a useful tool for the diagnosis of insomnia and for gaining insight into the therapeutic efficacy of hypnotic-sedative drugs.     

Oral airway resistance during wakefulness in eucapnic and hypercapnic sleep apnea syndrome

The purpose of this study was to evaluate whether there was an abnormal increase of upper airway resistance in the sitting and supine positions in hypercapnic obstructive sleep apnea syndrome (OSAS) patients compared with eucapnic OSAS or normal controls as measured by impulse oscillometry (IOS) while awake. Twenty subjects without OSAS served as controls (group I), and 20 patients with moderate or severe eucapnic OSAS (group II) and another eight hypercapnic severe OSAS patients (group III) were studied. Group II was further divided into two subgroups. Group IIa consisted of 14 subjects whose BMI was less than 35 and group IIb of six subjects whose BMI was greater than 35. All subjects also had an overnight sleep study. Oral airway resistance (AR) (including impedance (Zrs), resistance (R) and reactance (X)) was measured by impulse oscillometry (IOS) (MasterScreen IOS, VIASYS Healthcare GmbH, Germany) in the upright (seated) position and then in the supine position while awake. The results demonstrated that in both group I and group II, Zrs was normal in the sitting position. However, there was a high Zrs in the supine position for group II patients. In contrast, in group III patients, there was a high Zrs in both the sitting and supine positions. In conclusion, upper airway resistance was increased both sitting and supine in the hypercapnic OSAS patients; this would presumably increase the work of breathing and might explain why these subjects were hypercapnic while awake, while eucapnic OSAS patients and normal controls were not. Secondly, the increased upper airway resistance in the supine position in the eucapnic OSAS patients may contribute to their OSAS.     

The association of upper airway resistance with periodic limb movements

STUDY OBJECTIVES: We hypothesized that the upper airway resistance syndrome (UARS), the component event being a respiratory effort related arousal (RERA), and periodic limb movements in sleep (PLMS), the component event being repetitive, stereotyped extremity movements occurring in a periodic fashion, were associated in certain patients. DESIGN: Invasive polysomnography using Pes and full facemask pneumotachography was used to identify RERA's in patients. Periodic limb movements (PLM) were scored according to standard criteria and as associated with RERA if the movement occurred between the Pes nadir and the onset of the arousal. SETTING: A university hospital Sleep Disorders Laboratory. PARTICIPANTS: Patients consecutively diagnosed with PLMS in our sleep disorders laboratory over a 1 year period. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Fourteen of twenty patients demonstrated UARS in addition to PLMS (70%). In those 14, 63% of RERAs were associated with a PLM (mean = 51.7 + 36.2 PLM/RERAs per study vs 5.6 + 6.3 PLM/RERAs per study if the association were random). Patients with UARS had more arousals with their PLMs (P = 0.0006). CONCLUSIONS: An association exists between PLMS and UARS on both a group level and an event level. A high percentage of PLM with arousals correlated with breathing events due to increased effort in UARS; this may be of clinical utility in the management of PLMS patients.