Journal of Applied Physiology AJP: Gastrointestinal and Liver Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 91: 239-248, 2001;
8750-7587/01 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rowley, J. A.
Right arrow Articles by Badr, M. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rowley, J. A.
Right arrow Articles by Badr, M. S.
Vol. 91, Issue 1, 239-248, July 2001

Effect of REM sleep on retroglossal cross-sectional area and compliance in normal subjects

James A. Rowley, Carrie S. Sanders, Brian R. Zahn, and M. Safwan Badr

Medical Service, John D. Dingell Veterans Affairs Medical Center, and the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

It has been proposed that the upper airway compliance should be highest during rapid eye movement (REM) sleep. Evidence suggests that the increased compliance is secondary to an increased retroglossal compliance. To test this hypothesis, we examined the effect of sleep stage on the relationship of retroglossal cross-sectional area (CSA; visualized with a fiber-optic scope) to pharyngeal pressure measured at the level of the oropharynx during eupneic breathing in subjects without significant sleep-disordered breathing. Breaths during REM sleep were divided into phasic (associated with eye movement, PREM) and tonic (not associated with eye movements, TREM). Retroglossal CSA decreased with non-REM (NREM) sleep and decreased further in PREM [wake 156.8 ± 48.6 mm2, NREM 104.6 ± 65.0 mm2 (P < 0.05 wake vs. NREM), TREM 83.1 ± 46.4 mm2 (P = not significant NREM vs. TREM), PREM 73.9 + 39.2 mm2 (P < 0.05 TREM vs. PREM)]. Retroglossal compliance, defined as the slope of the regression CSA vs. pharyngeal pressure, was the same between all four conditions (wake -0.7 + 2.1 mm2/cmH2O, NREM 0.6 ± 3.0 mm2/cmH2O, TREM -0.2 ± 3.3 mm2/cmH2O, PREM -0.6 ± 5.1 mm2/cmH2O, P = not significant). We conclude that the intrinsic properties of the airway wall determine retroglossal compliance independent of changes in the neuromuscular activity associated with changes in sleep state.

upper airway; imaging; nasopharynx; rapid eye movement sleep


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

RAPID EYE MOVEMENT (REM) sleep is a distinct neurophysiological state associated with significant changes in breathing pattern and ventilatory control compared with both wakefulness and non-rapid-eye movement (NREM) sleep (4, 18, 37). Because data from sleep studies show that obstructive apneas are more frequent and longer during REM sleep (5, 30), it has been hypothesized that upper airway mechanics would also be influenced by REM sleep. We recently investigated the effect of REM sleep on retropalatal compliance during eupneic breathing by using an experimental system in which we simultaneously image the upper airway by use of a fiber-optic scope and measure the pharyngeal pressure (Pph) at the site of airway narrowing (25). Using this experimental approach, we found that retropalatal cross-sectional area (CSA) decreased significantly during NREM sleep but did not decrease further in either tonic (not associated with rapid eye movements) or phasic (associated with rapid eye movements) REM sleep (TREM and PREM, respectively). We also found that retropalatal compliance is highest during NREM sleep, with the compliance during TREM and PREM similar to that seen in wakefulness.

This result was unexpected for several reasons. First, upper airway neuromuscular activity, particularly of the genioglossus muscle, is lowest during REM sleep (26, 27, 42). Second, it has been shown that the genioglossus reflex to negative pressure is inhibited during REM sleep, resulting in an increased upper airway collapsibility in normal subjects during REM sleep (34). Third, it has recently been demonstrated that the site of obstruction during REM sleep in patients with obstructive sleep apnea is more often in the oropharynx than in the nasopharynx (2). Thus we hypothesized that one explanation for our findings of decreased compliance in REM sleep compared with NREM sleep was that we had studied the nasopharynx rather than the oropharynx. Thus in this work we investigated the effect of REM sleep on retroglossal CSA and compliance. Our hypothesis was that retroglossal compliance would be increased during REM compared with NREM sleep.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects

The experimental protocol was approved by the Human Investigation Committee of the Wayne State University School of Medicine and the Detroit Veterans Affairs Medical Center. Informed, written consent was obtained from all subjects. We studied 10 subjects who were recruited from the general population. Four subjects complained of light habitual snoring but did not have any sleep-disordered breathing (as evidenced by apneas or hypopneas) on baseline polysomnography. The anthropometric, polysomnographic, and clinical data are summarized in Table 1.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Anthropometric, polysomnographic and clinical data for each subject

REM Enhancement

We enhanced our ability to achieve REM sleep in heavily instrumented subjects in several ways. First, we severely restricted the sleep of our subjects before their study. Subjects were instructed to sleep no more than 5 h the night before the study and were then kept awake the night of the study until ~5-6 AM. Thus all subjects had been awake for ~24 h before the study. Second, we studied the subjects starting at 5:00 AM, which is the time of the day at which the majority of people have the highest propensity for REM sleep (3). Finally, we kept interruptions to a minimum after the initial data collection for wakefulness and NREM sleep. Seven of the 10 subjects underwent the above REM enhancement. The remaining three subjects were medical residents or students and were studied after an all-night call in the hospital.

Measurements

Electroencephalograms (EEG), electrooculograms (EOG), and chin electromyograms (EMG) were recorded (model 7-B, Grass) using the international 10-20 system of electrode placement (EEG: C3-A2 and C4-A1; EOG F7-A2 and F8-A2). Airflow was measured by a pneumotachometer (model 3700A, Hans Rudolph) attached to a nasal mask. Tidal volume (VT) was obtained from the integrated airflow signal. Airway pressures were measured using a pressure-tipped catheter (Model TC-500XG, Millar), which was threaded though the mask (see Protocols for positioning). The pharyngeal lumen was visualized by using a pediatric fiber-optic bronchoscope (FB10X, Pentax). Lidocaine (2%) was atomized into the pharynx through the mouth to provide retroglossal topical anesthesia, and 2% lidocaine jelly was used to provide both lubrication and anesthesia to the nostril through which the scope was passed. The position of the scope was standardized across subjects by advancing the tip to touch the tip of the epiglottis and then withdrawing it 2-3 cm. Slight variation of the orientation of the scope among subjects ensured clear visualization of the retroglossal lumen. Once the fiber-optic scope was positioned, it was secured by use of soft putty around the hole of the nasal mask through which it was passed. A continuous image of the retroglossal lumen was obtained from a closed-circuit video camera (Endovision 3000, Pentax Precision Instrument) connected to the scope. The video image and the respiratory signals were digitized at 5 frames/s and 25 Hz, respectively, by using specially developed software.

Protocols

Night 1: Airway visualization protocol. The subjects were sleep restricted as described above. All subjects were instructed to use oxymetazoline hydrochloride 0.05% (Goldline Laboratories) 12 h before the study start time. An additional dose was given before the start of the study if the subject had subjective nasal stuffiness. At ~5 AM, sleep-staging electrodes and respiratory bands were attached, and the subjects then lay supine in the bed. Local anesthesia was given, the pressure catheter was passed through one nostril, and the fiber-optic scope was then passed through the opposite nostril and positioned as described above. With use of the fiber-optic scope, the pressure catheter tip was positioned at the level of the oropharynx lumen to measure Pph. The nasal mask was then carefully lowered onto the face and secured. At this point, the exact position of the fiber-optic scope was adjusted, and the scope plus the attach video camera were placed in a clamp suspended above the subject's head. The mask was carefully sealed, including the hole through which the scope was inserted. A check for air leakage around the mask was made by occluding the airflow during an attempted inspiration and expiration. After a period of wakefulness during which 3-5 min of data were collected for analysis, the subject was allowed to go to sleep. During the sleep period, the subject's head position was fixed with the use of sand-filled bolsters.

All variables were continuously monitored throughout the study. The fiber-optic image and the respiratory signals were acquired to the computer on-line during wakefulness, stage 2 sleep, slow-wave sleep, and REM sleep. Data were acquired only during periods in which the retroglossal lumen was clearly visible (i.e., no secretions obscuring the image). The study was terminated after a period of stable REM sleep was achieved during which there was sufficient time to collect both clear fiber-optic images and respiratory signals.

Night 2: Pressure-flow relationship protocol. For this study, the subjects were requested to restrict their sleep to 6 h the night before the study, and the subject was studied beginning at 11 PM after ~18 h of sleep deprivation. Sleep staging electrodes and respiratory bands were attached. Supraglottic pressure was measured by positioning the pressure catheter tip in the hypopharynx by observing the tip of the catheter disappear behind the tongue. The subject was laid supine on the bed and the nasal mask was placed on the face and secured. A check for air leakage around the mask was made. The remaining transducers were then attached. After a period of wakefulness during which 3-5 min of data was collected for analysis, the subject was allowed to fall asleep. During this study, the subject's head position was not fixed. All variables were monitored continuously throughout the study, and respiratory signals were acquired onto the computer on-line during wakefulness, stage 2 sleep, slow-wave sleep, and REM sleep.

Data Analysis

Night 1. Wakefulness/sleep stage was scored according to standardized criteria (22). Inspired tidal volume (VT), inspiration time (TI), total breath duration (TT), breathing frequency (f), and inspired minute ventilation (VI) were calculated breath by breath during a period of wakefulness, stage 2 sleep, slow-wave sleep, and REM. Each breath during REM sleep was scored as either tonic REM (TREM) or phasic REM (PREM). PREM breaths were scored if a rapid EOG deflection >50 µV in amplitude occurred within the 1 s preceding inspiration or any time during the inspiratory cycle. TREM breaths were scored during periods of ocular quiescence between the phasic eye bursts (25, 42). For each of the five stages, ~6-12 breaths were analyzed. Breaths for analysis were selected during a period of time in which there was no arousal from sleep or any increase in EEG frequency and during which the retroglossal lumen was clearly visible. For the wake and NREM stages, consecutive breaths were obtained during a period in which the breathing was regular and stable. For the REM stages, breaths were selected in relation to eye bursts present (PREM) or absent (TREM).

The retroglossal CSA was obtained for each digitized frame (5 frames/s) by manually outlining the retroglossal lumen using computer software (SigmaScan, Jandel) as shown in Fig. 1. The landmarks for outlining included the base of the tongue anteriorly, the lateral pharyngeal walls, and the posterior pharyngeal wall at the level of the glottic opening. The epiglottis was also used as a reference landmark, generally by its location in the center of the outlined image. During this process, the investigator was blinded to the phase of respiration but not to the stage of sleep. The reproducibility of this technique has been previously validated by our laboratory (38). For each image, the scanning software provided an area in pixels. We converted these relative areas to absolute areas by using the dimensions of the pressure catheter as a reference (25).


View larger version (61K):
[in this window]
[in a new window]
  		Fig. 1.   Example of a fiber-optic image of the retroglossal airway with anatomic landmarks identified. Outline of the oropharyngeal lumen, used to calculate the cross-sectional area (CSA) is shown by the white line.

Retroglossal compliance (compliance of the upper airway; Cua) was determined as follows. We plotted the CSA of the digitized frames for each breath (both inspiration and expiration) against the Pph that corresponded to each image of that breath. We defined the Cua as the slope of the regression line, CSA vs. Pph. Inspiratory and expiratory Cua were determined in a similar fashion using only the CSA and Pph data for inspiration or expiration.

Night 2. Wakefulness/sleep stage was scored according to standardized criteria (22). Inspired VT, TI, TT, and VI were calculated for 10-15 breaths during a period of wakefulness, stage 2 sleep, slow-wave sleep, PREM, and TREM as described for night 1. A pressure-flow loop was plotted for each breath. All trials were averaged, and a composite pressure-flow loop was plotted for each subject. To generate a composite pressure-flow plot of breaths of different duration, pressure and flow were sampled at equally distributed points in both inspiration and expiration. Inspiratory resistance (Rua) at a fixed flow of 0.2 l/s was computed from each loop as a numeric representation of the linear part of the pressure-flow loop.

Additional analysis. Each of the 10 subjects also had 50-100 breaths analyzed for the presence of inspiratory flow limitation (IFL) as part of another research project. IFL was defined as a 1-cmH2O or greater decrease in supraglottic pressure without any corresponding increase in flow during inspiration. For each subject, the percentage of IFL breaths (%IFL) was calculated as the number of IFL breaths divided by total breaths. Each subject's %IFL is presented in Table 1.

Statistical Analysis

Night 1. All statistical analyses were performed on the complete data set of 10 subjects using SigmaStat2.0 (Jandel Scientific). Comparisons of the mean values TI, TT, VT, VI , f, and Cua, as well as the CSA at the beginning of inspiration (CSAI) were carried out by use of a one-way analysis of variance (ANOVA) with repeated measures, with sleep stage as the factor. To compare the inspiratory and expiratory Cua, we first changed all values to the absolute values because we were interested in comparing absolute changes in CSA per unit change in Pph; statistical analysis was then performed by using a two-way ANOVA with repeated measures, with sleep stage and phase of breath (inspiration or expiration) as the factor. For comparisons that reached significance (P < 0.05), post hoc analysis was performed by using the Student-Newman-Keuls method.

Night 2. All statistical analyses were performed on the data set of nine subjects. One subject (DW) relocated before participating in the resistance measurement night. Comparison of the mean values, TI, TT, VT, VI, and Rua were carried out by using a one-way ANOVA with repeated measures with sleep stage as the factor. For comparisons that reached significance (P < 0.05), post hoc analysis was performed by using the Student-Newman-Keuls method.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Table 1 presents demographic variables for each of the 10 subjects as well as the REM latency and number of minutes of REM for each subject. Resistance data for another subject (AC) was previously reported (25). Because of the similarities seen between stage 2 and slow-wave sleep on preliminary analysis and because we were most interested in comparing REM sleep to NREM sleep, we combined the data for stage 2 and slow-wave sleep into one category, NREM sleep, before the final statistical analyses were performed.

Effect of Sleep Stage on Ventilatory Data

The group mean levels for each respiratory variable during wakefulness and sleep stages for each of the two nights are shown in Table 2. For night 1, wakefulness was associated with a higher VI compared with each of the other three sleep stages (P < 0.001). The increased VI was secondary to an increased VT in wakefulness compared with the three sleep stages (P = 0.001). There was no difference in VI and VT between any of the sleep stages. There were no differences in f, TI, and TT between wake and any of the stages of sleep. For night 2, wakefulness was associated with a higher VT compared with the three sleep stages (P = 0.003). There was a trend toward an increased VI in wakefulness compared with the three sleep stages (P = 0.06). There were no differences between wakefulness and the sleep stages for f, TI, or TT.

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Respiratory variables during wakefulness and sleep

Effect of REM Sleep on CSA

The effect of sleep stage on the group mean CSAI is shown in Fig. 2. A one-way ANOVA with repeated measures indicated that sleep stage had a significant effect on CSAI (P < 0.001). Post hoc analysis showed that the mean CSAI became significantly smaller as the subjects progressed from wakefulness to NREM sleep (104.6 ± 65.0 vs. 156.8 ± 48.6 mm2 in wakefulness; P < 0.05). There was no significant difference between NREM and TREM sleep [83.1 ± 46.4 mm2, P = not significant (ns) compared with NREM] but there was a further decrease in CSA in PREM sleep (73.9 ± 39.2 mm2, P < 0.05 compared with TREM sleep).


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 2.   Baseline retroglossal cross-sectional area (CSAI) for each subject is plotted for wakefulness, non-rapid eye movement (NREM), tonic rapid eye movement (TREM), and phasic rapid eye movement (PREM) sleep. Mean ± SD is also shown for each stage (hexagon). *There was a significant effect of sleep stage on CSAI (P < 0.001). Post hoc analysis showed that the mean wake in CSAI was greater than in NREM; CSAI was the same in NREM and TREM sleep; and CSAI was larger in TREM than in PREM sleep (all P < 0.05).

Effect of REM Sleep on Cua

An example of the CSA-Pph curves for one subject is illustrated in Fig. 3A. The figure illustrates the near-linear relationship between CSA and Pph over the range of pressures that we are studying. The Cua was defined as the slope of the regression CSA vs. Pph. Therefore, the figure also illustrates that for this subject the airway compliance was near zero for wake, NREM, and REM sleep. The group mean CSA-Pph curves are illustrated in Fig. 3B. In wake, NREM, and PREM, CSA changed little over the change in pressure. There were larger changes in CSA during TREM, with an increase in CSA during early inspiration and narrowing in late expiration.


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 3.   A: retroglossal CSA is plotted against pharyngeal pressure (Pph) for one subject for wakefulness, NREM, TREM, and PREM sleep (see legend for line styles). Graph illustrates that CSA did not significantly change over the narrow range of Pph changes during observed eupneic breathing in any of the conditions studied. B: mean retroglossal CSA is plotted against mean Pph for 1 subject for wakefulness, NREM, TREM, and PREM sleep. Graph illustrates that, for the group as a whole, CSA did not significantly change over the narrow range of Pph changes observed during eupneic breathing in any of the conditions studied.

Individual and group mean retroglossal Cua for each stage of sleep are shown in Fig. 4. For the group as a whole, there was no significant effect of sleep stage on Cua (wake, -0.7 ± 2.1 mm2/cmH2O; NREM, -0.6 ± 3.0 mm2/cmH2O; TREM, -0.2 ± 3.3 mm2/cmH2O; and PREM -0.6 ± 5.1 mm2/cmH2O, P = ns). It should be noted that one subject with snoring and 95.8% flow-limited breaths (subject MP) did have a Cua > 10 mm2/cmH2O during PREM. However, the Cua of all other snoring subjects, in all stages of sleep, were <10 mm2/cmH2O. There was no correlation between the %IFL (Table 1) and Cua during any stage of sleep.


View larger version (12K):
[in this window]
[in a new window]
  		Fig. 4.   Retroglossal compliance (Cua) for each subject is plotted for wakefulness, NREM, TREM, and PREM sleep. Mean ± SD is also shown for each stage (hexagon). There was no significant effect of sleep stage on Cua (P = ns).

The effect of phase of respiration on Cua for each sleep stage is shown in Fig. 5. A two-way ANOVA with repeated measures found that neither sleep stage or phase of respiration had significant effects on Cua. In other words, the inspiratory Cua was not significantly different the expiratory Cua. The large standard deviations found for this set of data in expiration is largely due to two subjects, one with and one without habitual snoring, who had a larger Cua in expiration than in inspiration. There was no correlation between the Rua and Cua during any stage of sleep.


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 5.   Mean ± SD Cua for inspiration (solid bars) and expiration (shaded bars) is plotted for wakefulness and NREM, TREM, and PREM sleep. There was no effect of sleep stage or phase of respiration on Cua.

Effect of REM Sleep on Upper Airway Resistance

Resistance at a fixed flow during the linear part of the pressure-flow relationship was measured during the stages of sleep in 9 of the 10 subjects (Fig. 6). For the group of 9 subjects, Rua during NREM was 8.3 ± 11.4 cmH2O · l-1 · s-1, during TREM 3.8 ± 3.1 cmH2O · l-1 · s-1, and during PREM 4.7 ± 3.7 cmH2O · l-1 · s-1. There were no significant differences in Rua between the stages of sleep.


View larger version (9K):
[in this window]
[in a new window]
  		Fig. 6.   Upper airway resistance at fixed flow (Rua) for each subject is plotted for wakefulness, NREM, TREM, and PREM sleep. Mean ± SD is also shown for each stage (hexagon). There was no significant effect of sleep stage on Rua (P = ns).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The aim of the present study was to investigate the effect of REM sleep on retroglossal CSA and compliance in a group of subjects without significant sleep-disordered breathing. There were two main findings from our study. First, the retroglossal CSA was significantly smaller during PREM compared with NREM sleep, with no difference in CSA between NREM and TREM sleep. This is in contrast to our findings in the nasopharynx, where there was no further narrowing of the retropalatal airway in REM sleep compared with NREM sleep (25). Second, Cua during eupneic breathing, defined as the slope of the regression line for CSA plotted against Pph, was similar to that during wakefulness in all stages of sleep. These findings indicate that, in a group of subjects without significant sleep-disordered breathing, the oropharynx was equally noncompliant during wakefulness and NREM and REM sleep.

Validity of Techniques and Methodology

Fiber-optic endoscopy has several limitations that need to be considered when interpreting the findings. These have been discussed in detail in earlier papers (19, 25). Briefly, CSA measurements could be influenced by movement of the fiber-optic scope. To prevent this, the orientation of the scope was fixed by anchoring it to the mask, the position of the subject's head was fixed by a sand pillow, and only images in which there was judged to be no change in the relationship of the scope to anatomic landmarks in different planes were analyzed. Second, an important consideration is the ability to accurately and reproducibly detect the edge of the airway lumen. To ensure this, only images in which the airway lumen was clearly visible were analyzed. Third, only 6-12 images were analyzed per stage of sleep. Reasons for the limited number of breaths included the need to manually outline the pharyngeal lumen of each image, poor visualization of the pharyngeal lumen, and, for REM, a limited number of breaths available to analyze because of the criteria used to choose phasic and tonic breaths and because we had only one REM period for each subject. Despite the small numbers, we believe that the images analyzed are representative because of the similarity of changes in CSA and the lack of change in Cua across the 10 subjects. In addition, we note that the CSA values we obtained were similar to values obtained by other investigators using fiber-optic imaging (11), computerized tomography (29), and acoustic reflection (17).

We note that four of the subjects had short REM periods lasting 2 min or less. However, we believe that the breaths chosen for analysis are representative because other investigators have shown that the effects of REM sleep on ventilatory parameters and cardiovascular flow are related to the rapid eye movements and occur with the onset of REM sleep (12, 42).

A potential limitation of our study protocol is that we sleep deprived the subjects. Sleep deprivation has been shown to result in an increase in snoring and sleep-disordered breathing (16). However, we do not believe that the sleep deprivation influenced our results. First, if sleep deprivation increases sleep-disordered breathing, we would have expected more compliant airways in our subjects. Second, Leiter et al. (16) studied the effect of 24-h sleep deprivation on genioglossus EMG activity and found that sleep deprivation decreased the genioglossus EMG response to CO2 rebreathing but only in subjects older than 30 years of age; 8 of our 10 subjects were under 30 years of age. Finally, Series et al. (33) found that the critical closing pressure of the upper airway did not change after 24 h of sleep deprivation, suggesting that global upper airway neuromuscular activity was unchanged after sleep deprivation.

The measurement of pharyngeal compliance as defined requires several assumptions. First, we are not measuring true pharyngeal airway compliance, because measurement of pharyngeal volume in sleeping, spontaneously breathing subjects is not practical. We believe that pharyngeal CSA is a reasonable substitute, as have others who have measured Cua (10, 15). Second, an accurate compliance measurement using area requires that the pressure be measured at the same level as the changes in area, as we have done in this study. Third, the measurement of compliance assumes that the pressure being measured is a transmural pressure because the extraluminal pressure is assumed to be constant (15, 20). Finally, the relative contributions to the transmural pressure (23), such as the pressure intrinsic to the airway wall (attributed mostly to the upper airway muscles) and the pressure surrounding the airway (attributed to structures such as the tongue, tonsils, and pharyngeal fat pads) cannot be ascertained with this method, primarily because it is difficult to measure the pressure surrounding the airway in a human.

It must be noted that we made pharyngeal compliance measurements over a small range of Pph (~4-5 cmH2O) because we were specifically interested in studying the effect of REM sleep on compliance during eupneic breathing. Thus the compliance measurements may be different from those made by experimentally manipulating the Pph with externally applied pressure over a larger range of pressures (~10-20 cmH2O) (10, 15). By measuring compliance in this fashion in the static upper airway, it has been observed that the pharyngeal compliance changes with the pharyngeal CSA (10, 11). Because the upper airway is a dynamic structure, we believe that the measurement of Cua is best made during eupneic breathing and that this approach allows us to make unique observations on the effect of sleep stage on the upper airway.

Our study was based on the premise the genioglossus muscle activity is reduced during REM sleep. Older investigations (26, 27) showed decreases in tonic activity of the genioglossus and other upper airway muscles during REM sleep. Recent work showed a decrease in genioglossus peak inspiratory activity between NREM and PREM sleep but not between NREM and TREM sleep (42). Recently it has also been shown that the reflex increase in genioglossus activity to negative pressure is decreased in REM sleep (34). Overall, the evidence suggests that genioglossus activity decreases in REM sleep, particularly in PREM sleep. In addition, we have made the assumption that a potential increased resistive load secondary to the fiber-optic scope has not resulted in a compensatory increase in upper airway neuromuscular activity needed to maintain airway caliber (7). This assumption is based on two investigations that show no increase in genioglossus activity during inspiratory resistive loading (9, 21). However, we did not make any direct measurements of muscle activity, particularly of the genioglossus muscle. This was for practical reasons because further interventions may interfere with sleep, especially REM sleep. It is also unclear whether the measurement of one particular muscle would be adequate to make correlations between EMG activity and mechanical output given the complexity of the upper airway and the multiple muscles involved in determining CSA and compliance. However, the lack of EMG measurements precludes drawing firm conclusions regarding the effect of upper airway dilators on upper airway CSA and compliance.

Effect of REM Sleep on the Retroglossal Airway

The finding of decreasing CSA as the subjects progressed from wakefulness to NREM sleep to PREM sleep without changes in retroglossal compliance suggests that airway patency and compliance are determined by different factors in the oropharynx. Because the tongue comprises the anterior wall of the oropharynx, it would be expected that the retroglossal CSA is primarily determined by the genioglossus muscle. Several studies have shown that passive maneuvers that move the tongue forward dilate the airway (35), as does stimulation of the genioglossus muscle (14, 28, 36). Alternatively, inhibition of genioglossus activity would be expected to result in decreased airway patency. We note a correlation between the decreased peak genioglossus activity in PREM sleep compared with TREM sleep found by Wiegand et al. (42) and our decreased CSA in PREM sleep compared with TREM and NREM sleep. Thus our data supports the conclusion that genioglossus activity is a determinant of retroglossal CSA.

Retroglossal compliance, however, did not change between wakefulness and any stage of sleep, including PREM sleep. Compliance was also the same between inspiration and expiration, despite the phasic activity present during inspiration. This suggests that the neuromuscular activity, including the phasic activity, of the genioglossus is not a determinant of upper airway stiffness. The dissociation between CSA and compliance that we have noted is consistent with the work of previous investigators. In an isolated upper airway model in dogs, it has been shown that upper airway muscle activation leads to dilation of the upper airway (36). However, activation did not result in a shift of the slope of the pressure-volume curve (6). Schnall et al. (28) determined that electrical stimulation of the genioglossus did not result in decreased Rua during eupneic breathing in normal awake subjects. Although CSA was not directly measured, Rowley and colleagues showed that passive movement of the tongue (23) and hypoglossal nerve transection (24) did not change the critical closing pressure in a feline isolated upper airway model, suggesting that the genioglossus muscle plays a minor role in upper airway collapsibility. We conclude that these studies, in addition to our present data, suggest that genioglossus activity is an important determinant of airway CSA but not of Cua or collapsibility. Instead, retroglossal compliance is likely determined by the nonneuromuscular properties of the airway wall. In the oropharynx, which is dominated by the tongue, the intrinsic stiffness of the genioglossus is the most likely determinant of the nonneuromuscular properties.

In summary, our results indicate that the genioglossus is an important determinant of retroglossal structure and function but that influence is different for CSA and compliance. The size of the oropharynx is influenced by genioglossus neuromuscular activity, as evidenced during PREM sleep in which there is both decreased activity and decreased patency. In contrast, during the respiratory cycle, the nonneuromuscular properties of the genioglossus favor airway stiffness resulting in a low retroglossal compliance.

Retropalatal vs. Retroglossal CSA and Compliance

The results of this study contrasted in several important ways from our findings in the nasopharynx (25). First, in the nasopharynx we found that the CSA was decreased in NREM sleep compared with wakefulness but did not decrease further in REM sleep. Retropalatal CSA is primarily determined by the muscles of the palate, including the tensor and levator palatini muscles. The neuromuscular activity of both of these muscles has been shown to decrease significantly during NREM sleep (39, 40). If neuromuscular activity is the key determinant of upper airway size as proposed above, the results could indicate that although neuromuscular activity to retroglossal muscles (such as the genioglossus) decreases during REM sleep, the neuromuscular activity of muscles important to retropalatal CSA does not decrease. This has not been studied recently in a systematic fashion, but an older study suggests that there is no neuromuscular activity of these muscles during REM sleep (27). Therefore, nonneuromuscular properties of the upper airway must also influence baseline CSA in the nasopharynx. Nonneuromuscular determinants of upper airway size include the intrinsic properties of the muscles, connective tissue, and bony structures. We have previously hypothesized that increased blood flow to the nasopharynx during REM sleep increased the stiffness of the nasopharynx during REM. Theoretically, this increased stiffness could act to enlarge the retropalatal CSA. Alternatively, the bony structures of the nasopharynx, including the pterygoid hamulus, could act to keep the airway open during periods of decreased neuromuscular activity.

Second, retroglossal compliance did not change between sleep stages, whereas we previously found that retropalatal compliance was increased during NREM sleep compared with REM sleep. Because of the absence of neuromuscular activity in REM sleep, we hypothesized that nonneuromuscular properties of the upper airway wall, particularly the vascular perfusion of the upper airway, were the principal determinants of retropalatal stiffness in REM compared with NREM sleep. Our present data would indicate that nonneuromuscular properties are the primary determinants of retroglossal compliance during all stages of sleep. The difference in our findings for the two different sites is likely because of the large influence the tongue plays in the oropharynx. In particular, we speculate that the stiffness of this large muscle may not be influenced by changes in vascular perfusion as is the stiffness of relatively thin muscles such as the tensor and levator palatini.

Implications

Our findings have several important implications regarding the determinants of Cua in the sleeping human. First, sleep stage has differential effects on upper airway structure and function depending on the site of upper airway investigated. This would indicate that the study of either area in isolation may not allow the proper insight on overall upper airway pathophysiology. Therefore, studies investigating the role of neuromuscular activity in upper airway function should include muscles that are found in both the nasopharynx (such as the tensor palatini) and the oropharynx (such as the genioglossus). Additionally, other measures of upper airway function, such Rua, critical closing pressure, or response to inspiratory resistance loading, may provide a better measure of upper airway mechanics because they measure the overall function of the upper airway, not just that of the nasopharynx or oropharynx.

Second, given the decrease in retroglossal CSA during REM sleep, it would be expected that Rua would increase during REM sleep as well. However, our own present data and those of other investigations show that Rua is the same or decreased during REM sleep (8, 25, 41). This finding of unchanged resistance despite decreasing CSA has two potential explanations. First, Rua may be determined primarily by the pharyngeal narrowing at the nasopharynx, not at the oropharynx. Because retropalatal CSA does not change between NREM and REM sleep, it would be expected that there would be no change in resistance. Second, it is possible that Rua and CSA do not correlate despite the known effect of increasing resistance with decreasing radius of a tube. That relationship is based on a solid, uniform tube. Given that the upper airway is not a solid or uniform structure, there could be additional determinants of resistance.

Third, as discussed above, the differential effect of REM sleep on retroglossal CSA and compliance indicates that upper airway neuromuscular activity is an important determinant of retroglossal CSA but not of compliance. In other words, the genioglossus dilates but does not stiffen the upper airway. Thus, when researchers use the term "upper airway dilator" for the genioglossus, it is important to realize that the effect of the genioglossus is on upper airway CSA only. Because there were minimal changes in CSA during eupneic breathing in both wake and sleep, we believe that our data support the conclusion that the main mechanical corollary of phasic inspiratory activity is to prevent further narrowing of the airway, rather than to open the airway, during inspiration (1).

Fourth, the relatively noncompliant airway in all stages of sleep, despite known changes in neuromuscular activity (26, 42) and the finding of similar compliance in inspiration and expiration, all support the conclusion that the nonneuromuscular properties, not neuromuscular activity, are the critical determinants of retroglossal compliance during sleep. Nonneuromuscular determinants of airway wall stiffness include the tissue characteristics of the airway wall muscles, which have been shown to correlate with passive muscle elastance (31, 32). Other nonneuromuscular determinants could include the connective tissues, caudal tracheal traction (23), and tissue blood perfusion (13).

In conclusion, our study has shown that baseline retroglossal CSA progressively decreases during NREM and REM sleep and that eupneic breathing during REM sleep is associated with a similar retroglossal compliance compared with that during wakefulness and NREM sleep. Our data suggest that the neuromuscular activity of the genioglossus is an important determinant of retroglossal CSA but that intrinsic properties of the airway wall determine retroglossal compliance independent of changes in the neuromuscular activity. We believe that these data on retroglossal compliance confirm our previous hypothesis that the nonneuromuscular properties of the airway wall are a more important determinant of upper airway stiffness during sleep than is upper airway neuromuscular activity. Future research should be directed at elucidating which mechanical properties are critical to determining Cua.


    FOOTNOTES

Address for reprint requests and other correspondence: J. A. Rowley, Wayne State Univ. School of Medicine, Sleep Disorders Center at Hutzel Hospital, 4707 St. Antoine, 1 Center, Detroit, MI 48201 (E-mail: jrowley{at}intmed.wayne.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7 September 2000; accepted in final form 29 January 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Badr, MS. Pathophysiology of upper airway obstruction during sleep. Clin Chest Med 19: 21-32, 1998[ISI][Medline].

2.   Boudewyns, AN, Van de Hayning PH, and De Backer WA. Site of upper airway obstruction in obstructive apnoea and influence of sleep stage. Eur Respir J 10: 2566-2572, 1997[Abstract].

3.   Carskadon, MA, and Dement WC. Normal human sleep: an overview. In: The Principles and Practice of Sleep Medicine, edited by Dement WC, Kryger MH, and Roth T.. Philadelphia, PA: Saunders, 2000, p. 15-25.

4.   Douglas, NJ. Control of ventilation during sleep. In: The Principles and Practice of Sleep Medicine, edited by Dement WC, Kryger MH, and Roth T.. Philadelphia, PA: Saunders, 2000, p. 229-241.

5.   Findley, LJ, Wilhoit SC, and Suratt PM. Apnea duration and hypoxemia during REM sleep in patients with obstructive sleep apnea. Chest 87: 432-436, 1985[Abstract/Free Full Text].

6.   Fouke, JM, Teeter JP, and Strohl KP. Pressure-volume behavior of the upper airway. J Appl Physiol 61: 912-918, 1986[Abstract/Free Full Text].

7.   Henke, KG, Badr MS, Skatrud JB, and Dempsey JA. Load compensation and respiratory muscle function during sleep. J Appl Physiol 72: 1221-1234, 1992[Abstract/Free Full Text].

8.   Hudgel, DW, Martin RJ, Johnson B, and Hill P. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol 56: 133-137, 1984[Abstract/Free Full Text].

9.   Hudgel, DW, Mulholland M, and Hendricks C. Neuromuscular and mechanical responses to inspiratory resistive loading during sleep. J Appl Physiol 63: 603-608, 1987[Abstract/Free Full Text].

10.   Isono, S, Morrison DL, Launois SH, Feroah TR, Whitelaw WA, and Remmers JE. Static mechanics of the velopharynx of patients with obstructive sleep apnea. J Appl Physiol 75: 148-154, 1993[Abstract/Free Full Text].

11.   Isono, S, Remmers JE, Tanaka A, Sho Y, Sato J, and Nishino T. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 82: 1319-1326, 1997[Abstract/Free Full Text].

12.   Kirby, DA, and Verrier RL. Differential effects of sleep stage on coronary hemodynamic function. Am J Physiol Heart Circ Physiol 256: H1378-H1383, 1989[Abstract/Free Full Text].

13.   Kitabatake, A, and Suga H. Diastolic stress-strain relation of nonexcised blood-perfused canine papillary muscle. Am J Physiol Heart Circ Physiol 234: H416-H420, 1978[Abstract/Free Full Text].

14.   Kobayashi, I, Perry A, Rhymer J, Wuyam B, Hughes P, Murphy K, Innes JA, McIvor J, Cheesman AD, and Guz A. Inspiratory coactivation of the genioglossus enlarges retroglossal space in laryngectomized humans. J Appl Physiol 80: 1595-1604, 1996[Abstract/Free Full Text].

15.   Kuna, ST, Bedi DG, and Ryckman C. Effect of nasal airway positive pressure on upper airway size and configuration. Am Rev Respir Dis 138: 969-975, 1988[ISI][Medline].

16.   Leiter, JC, Knuth SL, and Bartlett D. The effect of sleep deprivation on activity of the genioglossus muscle. Am Rev Respir Dis 132: 1242-1245, 1985[ISI][Medline].

17.   Martin, SE, Mathur R, Marshall I, and Douglas NJ. The effect of age, sex, obesity and posture on upper airway size. Eur Respir J 10: 2087-2090, 1997[Abstract].

18.   Millman, RP, Knight H, Kline LR, Shore ET, Chung DC, and Pack AI. Changes in compartmental ventilation in association with eye movements during REM sleep. J Appl Physiol 65: 1196-1202, 1988[Abstract/Free Full Text].

19.   Morrell, MJ, and Badr MS. Effects of NREM sleep on dynamic within-breath changes in upper airway patency in humans. J Appl Physiol 84: 190-199, 1998[Abstract/Free Full Text].

20.   Olson, LG, Fouke JM, Hoekje PL, and Strohl KP. A biomechanical view of upper airway function. In: Respiratory Function of the Upper Airway, edited by Mathew OP, and Sant'Ambrogio G.. New York: Marcel Dekker, 1988, p. 359-389.

21.   Pillar, G, Malhotra A, Fogel R, Beauregard J, Schnall R, and White DP. Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender. Am J Respir Crit Care Med 162: 1627-1632, 2000[Abstract/Free Full Text].

22.   Rechtschaffen, A, and Kales AA. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: National Institutes of Health, 1968.

23.   Rowley, JA, Permutt S, Willey S, Smith PL, and Schwartz AR. Effect of tracheal and tongue displacement on upper airway airflow dynamics. J Appl Physiol 80: 2171-2178, 1996[Abstract/Free Full Text].

24.   Rowley, JA, Williams BC, Smith PL, and Schwartz AR. Neuromuscular activity and upper airway collapsibility. Mechanisms of action in the decerebrate cat. Am J Respir Crit Care Med 156: 515-521, 1997[Abstract/Free Full Text].

25.   Rowley, JA, Zahn BK, Babcock MA, and Badr MS. The effect of rapid eye movement (REM) sleep on upper airway mechanics in normal human subjects. J Physiol (Lond) 510: 963-976, 1998[Abstract/Free Full Text].

26.   Sauerland, EK, and Harper RM. The human tongue during sleep: electromyographic activity of the genioglossus muscle. Exp Neurol 51: 160-170, 1976[ISI][Medline].

27.   Sauerland, EK, Orr WC, and Hairston LE. EMG patterns of oropharyngeal muscles during respiration in wakefulness and sleep. Electromyogr Clin Neurophysiol 21: 307-316, 1981[Medline].

28.   Schnall, RP, Pillar G, Kelson SG, and Oliven A. Dilatory effects of upper airway muscle contraction induced by electrical stimulation in awake humans. J Appl Physiol 78: 1950-1956, 1995[Abstract/Free Full Text].

29.   Schwab, RJ, Gefter WB, Hoffman EA, Gupta KP, and Pack AI. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis 148: 1385-1400, 1993[ISI][Medline].

30.   Series, F, Cormier Y, and LaForge J. Influence of apnea type and sleep stage on nocturnal postapneic desaturation. Am Rev Respir Dis 141: 1522-1526, 1990[ISI][Medline].

31.   Series, F, Cote C, Simoneau JA, Gelinas Y, St. Pierre S, Leclerc J, Ferland R, and Marc I. Physiologic, metabolic, and muscle fiber type characteristics of musculus uvulae in sleep apnea hypopnea syndrome and in snorers. J Clin Invest 95: 20-25, 1995.

32.   Series, F, Cote C, and St. Pierre S. Dysfunctional mechanical coupling of upper airway tissues in sleep apnea. Am J Respir Crit Care Med 159: 1551-1555, 1999[Abstract/Free Full Text].

33.   Series, F, Roy N, and Marc I. Effects of sleep deprivation and sleep fragmentation on upper airway collapsibility in normal subjects. Am J Respir Crit Care Med 150: 481-485, 1994[Abstract].

34.   Shea, SA, Edwards JK, and White DP. Effect of wake-sleep transitions and rapid eye movement sleep on pharyngeal muscle response to negative pressure in humans. J Physiol (Lond) 520: 897-908, 1999[Abstract/Free Full Text].

35.   Shelton, RL, and Bosma JF. Maintenance of the pharyngeal airway. J Appl Physiol 17: 209-214, 1962[Abstract/Free Full Text].

36.   Strohl, KP, and Fouke JM. Dilating forces on the upper airway of anesthetized dogs. J Appl Physiol 58: 452-458, 1985[Abstract/Free Full Text].

37.   Sullivan, CE, Murphy E, Kozar LF, and Phillipson EA. Ventilatory responses to CO2 and lung inflation in tonic versus phasic REM sleep. J Appl Physiol 47: 1304-1310, 1979.

38.   Taha, BH, Morrel MJ, Werkheiser M, and Badr MS. Simultaneous digitization of upper airway fiber-optic images and respiratory signals. Sleep 20: 883-890, 1997[ISI][Medline].

39.   Tangel, DJ, Mezzanote WS, and White DP. Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol 70: 2574-2581, 1991[Abstract/Free Full Text].

40.   Tangel, DJ, Mezzanote WS, and White DP. Influences of NREM sleep on activity of palatoglossus and levator palatini muscles in normal men. J Appl Physiol 78: 689-695, 1995[Abstract/Free Full Text].

41.   Wiegand, L, Zwillich CW, and White DP. Collapsibility of the human upper airway during normal sleep. J Appl Physiol 66: 1800-1808, 1989[Abstract/Free Full Text].

42.   Wiegand, L, Zwillich CW, Wiegand D, and White DP. Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men. J Appl Physiol 71: 488-497, 1991[Abstract/Free Full Text].

J APPL PHYSIOL 91(1):239-248
8750-7587/01 $5.00 Copyright © 2001 the American Physiological Society


This article has been cited by other articles:


Home page
 J. Neurophysiol.Home page
E. F. Bailey, K. W. Fridel, and A. D. Rice
Sleep/Wake Firing Patterns of Human Genioglossus Motor Units
J Neurophysiol, December 1, 2007; 98(6): 3284 - 3291.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. A. Rowley, I. Deebajah, S. Parikh, A. Najar, R. Saha, and M. S. Badr
The influence of episodic hypoxia on upper airway collapsibility in subjects with obstructive sleep apnea
J Appl Physiol, September 1, 2007; 103(3): 911 - 916.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. J. Armstrong, M. S. Leigh, D. D. Sampson, J. H. Walsh, D. R. Hillman, and P. R. Eastwood
Quantitative Upper Airway Imaging with Anatomic Optical Coherence Tomography
Am. J. Respir. Crit. Care Med., January 15, 2006; 173(2): 226 - 233.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
K. F. Mansour, J. A. Rowley, and M. S. Badr
Measurement of pharyngeal cross-sectional area by finite element analysis
J Appl Physiol, January 1, 2006; 100(1): 294 - 303.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
R. J. Schwab
Pro: Sleep Apnea Is an Anatomic Disorder
Am. J. Respir. Crit. Care Med., August 1, 2003; 168(3): 270 - 271.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
Rebuttal from Dr. Schwab
Am. J. Respir. Crit. Care Med., August 1, 2003; 168(3): 272 - 273.
[Full Text]

Home page
 J. Appl. Physiol.Home page
J. A. Rowley, C. S. Sanders, B. R. Zahn, and M. S. Badr
Gender differences in upper airway compliance during NREM sleep: role of neck circumference
J Appl Physiol, June 1, 2002; 92(6): 2535 - 2541.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
J. A. Rowley, X. Zhou, I. Vergine, M. A. Shkoukani, and M. S. Badr
Influence of gender on upper airway mechanics: upper airway resistance and Pcrit
J Appl Physiol, November 1, 2001; 91(5): 2248 - 2254.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar