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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The structural properties of the upper airway determine its collapsibility during periods of muscle hypotonia. Both rapid-eye-movement (REM) sleep and increases in nasal pressure (PN) produce hypotonia, which persists even after nasal pressure is abruptly reduced. To determine the factors that influence the collapsibility of the hypotonic airway, the critical pressure (Pcrit) and nasal resistance upstream to the site of pharyngeal collapse (RN) were measured in the first three breaths after abrupt reductions in PN during non-REM and REM sleep. PN was reduced abruptly from 15.2 ± 3.2 cm H2O (mean ± SD) for three breaths in 19 apneic patients. Upper-airway pressure-flow relationships were analyzed to determine Pcrit for each breath in non-REM and REM sleep. We found that Pcrit rose (collapsibility increased, p < 0.001) and RN fell (p = 0.02) between the first and third breath after the decrease in PN, whereas no difference in Pcrit was detected between sleep stages. In six patients, genioglossus-muscle electromyograms (EMGs) were recorded. Peak phasic activity rose between the first and third breath (p = 0.03), but tonic and peak phasic EMG activity fell in REM as compared with non-REM sleep (p < 0.001). We conclude that the hypotonic upper airway becomes most collapsible by the third breath after an abrupt decrease in PN, regardless of sleep stage and despite an increase in genioglossus-muscle activity. Our findings suggest that predominantly mechanical rather than neuromuscular factors modulate the properties of the pharynx after abrupt reductions in nasal pressure.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It is now well recognized that increases in pharyngeal collapsibility lead to airflow obstruction during sleep (1). When a moderate increase in pharyngeal collapsibility occurs, airflow obstruction is associated with continuous rhythmic snoring during sleep. As pharyngeal collapsibility increases progressively, more severe degrees of airflow obstruction have been associated with the development of periodic hypopneas and apneas during sleep. Therefore, increasing degrees of airflow obstruction during sleep are related to increases in pharyngeal collapsibility across a spectrum from health to disease.
The mechanism for increases in pharyngeal collapsibility are not well understood. One possibility is that such increases are related to disturbances in pharyngeal neuromuscular control. This possibility is suggested by animal studies that have demonstrated increases in collapsibility as pharyngeal neuromuscular activity wanes (5). It is therefore possible that such reductions in pharyngeal neuromuscular activity lead to increases in collapsibility in apneic patients (8). Alternatively, increases in pharyngeal collapsibility may be due to anatomic narrowing of the airway by pharyngeal structures (9, 10). Investigators have suggested that neuromuscular responses help maintain patency in an anatomically narrowed airway (11- 13). Consequently, it is possible that structural alterations rather than reductions in neuromuscular activity account for increases in pharyngeal collapsibility in apneic patients.
To examine the structural basis for alterations in pharyngeal collapsibility, investigators have studied pharyngeal biomechanics during periods of reduced or absent neuromuscular activity (7, 14). In one recent study, neuromuscular activity was eliminated with neuromuscular blocking agents in order to determine the influence of mandibular position on pharyngeal biomechanics (16). Although the routine use of such agents is hampered by practical considerations, physiologic alternatives exist for reducing pharyngeal neuromuscular activity. For example, it is known that marked reductions in pharyngeal neuromuscular activity occur during rapid-eye-movement (REM) sleep (17). In addition, studies have demonstrated hypotonia of the pharyngeal muscles with the application of positive nasal pressure during sleep (18), and have shown that this hypotonia persists even after the nasal pressure is abruptly reduced (15, 19). Therefore, it should be possible to examine the influence of passive anatomic structures on pharyngeal collapsibility in sleeping apneic patients after increasing the nasal pressure, particularly during REM sleep.
The present study was undertaken to examine factors that influence the collapsibility of the hypotonic upper airway of apneic patients. Pharyngeal collapsibility was measured by determining the level of nasal pressure below which the pharynx closed (critical pressure Pcrit). Current evidence suggests that the most hypotonic state occurs in the first breath after an abrupt reduction in nasal pressure (15), particularly during REM sleep (17). Therefore, we hypothesized that pharyngeal collapsibility would be greatest in this breath as compared with subsequent breaths and compared with non-REM sleep. In the present study, we determined Pcrit after reducing nasal pressure for three breaths repeatedly during non-REM and REM sleep. We then examined the mechanism for differences between breaths and sleep states.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject Selection
Patients from the Johns Hopkins Sleep Disorder Center who had obstructive sleep apnea (OSA) were selected on the basis of results of standard polysomnography (20). Patients with an apnea-hypopnea index (AHI) of more than 10 episodes per hour of non-REM and REM sleep were selected. In total, Pcrit was measured in 19 patients. In six of the patients, genioglossal electromyographic activity (EMGgg) was also monitored. Patients with underlying cardiac or pulmonary disease were excluded. This protocol was approved by the Johns Hopkins Institutional Review Board.
Experimental Setup
All patients underwent routine polysomnographic monitoring of sleep, with bilateral electrooculograms (EOGs) electroencephalograms (EEGs) (C3-A2 and C3-O1), and submental EMGs. A standard Hyatt-type esophageal balloon catheter was passed perinasally and utilized for monitoring esophageal pressure (Pes). The patients were fitted with a nasal mask that was affixed to the face with a sealing compound. Pressure was monitored in the nasal mask (PN). Airflow was monitored with a pneumotachometer (Hans Rudolph, Kansas City, MO) and differential pressure transducer (Validyne ± 2 cm H2O; Northridge, CA). In selected patients, EMGgg was monitored with fine wire-hook needle electrodes placed sublingually. The raw and moving average EMGgg were monitored (Moving Averager, time constant 200 ms; Charles Ward Enterprises, Ardmore, PA).
Equipment was designed to maintain constant levels of PN and to
abruptly change from one level of PN to another over the range from
15 to +20 cm H2O. Both a bilevel positive-pressure source (BiPAP;
Respironics, Murrysville, PA) and a negative pressure source (modified REM-Star; Respironics) were utilized for this purpose. These
pressure sources were connected to a valve that could be turned manually to toggle between the two sources. The outflow from this valve
was then connected in series to the pneumotachometer and nasal
mask described earlier.
Initially, a high level of positive pressure was applied to the nasal circuit by setting this pressure with the BiPAP unit in the inspiratory positive airway pressure (IPAP) mode. We were then able to reduce the circuit pressure abruptly in one of two ways. When decreasing pressure within the positive pressure range, a lower expiratory positive airway pressure (EPAP) level was preset. The BiPAP unit was then switched from the IPAP to the EPAP mode for three breaths, and then once again switched back to the IPAP mode. When decreasing the pressure from a positive to a negative level, the level of subatmospheric pressure was preset in the modified REM-Star unit. The valve could then be turned, thereby changing from the positive to the negative pressure source. The valve could then be turned back to the positive pressure source after three breaths.
Protocol
All patients were monitored in the supine position with a pillow placed under the head. The patients were allowed to enter sleep while PN was maintained at a mean "holding" PN of 15.2 ± 3.2 cm H2O. This PN level was chosen so as to abolish inspiratory airflow limitation, as previously described (1, 21, 22). During stable periods of both non-REM and REM sleep, PN was abruptly reduced for three breaths before being increased to the holding PN thereafter. The PN was reduced repeatedly to several levels encompassing the level of PN at which airflow first ceased (Pcrit). Such reductions in PN were repeated approximately 10 to 15 times at one minute intervals during both non-REM and REM sleep. When abrupt decreases in PN were associated with arousals from sleep, the patients were allowed to return to stable sleep for several minutes before PN was again reduced. These data were excluded from analysis.
Data Analysis
With each reduction in PN, three consecutive breaths were analyzed.
Initially, the inspiratory airflow (
I) and Pes signals were examined.
When I reached a maximal level (Imax) and plateaued as Pes fell
progressively, limitation in I was considered to be present (Figure
1). For these flow-limited inspirations, Imax and PN were measured
for each breath at each level of PN tested. Data were obtained for the
first, second, and third breath at each PN level during both non-REM
and REM sleep.
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The relationship between Imax and PN was then examined (Figure
2), and the least-squares linear regression equation for the relationship was computed (Minitab Inc., State College, PA). The regression
equation was then solved for Pcrit (the PN at which Imax became
zero). The nasal resistance (RN) upstream of the site of pharyngeal
collapse was also calculated as the reciprocal of the slope of the regression equation, as previously described (21).
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In six patients, tonic and peak phasic EMGgg activity was also measured for each breath at each level of PN and each sleep state, and for the breath before the PN was reduced from the holding pressure. EMGgg activity was expressed as a percent of the maximum level recorded for each patient during sleep for the entire study.
For each outcome variable (Pcrit, RN, tonic and peak phasic EMGgg), two-factor analysis of variance (ANOVA) was utilized (Minitab). The breath number and sleep stage were treated as fixed factors, and patients were treated as a random factor. Pearson correlation coefficients were computed for comparisons between sleep states. A value of p < 0.05 was considered significant. Values are reported as means ± SD.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Anthropometrics and Polysomnographic Parameters
A group of 19 apneic patients were selected for study (Table 1). There were 16 males and three females in this group. The group was obese, with a body mass index (BMI) of 41.1 ± 7.5 kg/m2. In initial sleep studies, the group had clear-cut OSA during both non-REM (AHI = 75.4 ± 26.5 episodes/h) and REM (AHI = 70.7 ± 19.3 episodes/h) sleep.
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Pcrit and RN
In Figure 3, Pcrit measurements for the first, second, and third
breath after an abrupt decrease in PN from holding pressure are shown for non-REM and REM sleep. ANOVA revealed a
significant increase in Pcrit from the first through the third
breath (p < 0.001). An overall increase in Pcrit from 1.2 ± 3.9 cm H2O to 1.4 ± 2.9 cm H2O was observed between the
first and third breaths after abrupt reductions in PN. These
breath-to-breath increases in Pcrit were not related to differences in inspiratory swings in Pes, which did not change significantly from breath 1 (10.6 ± 3.9 cm H2O) to breath 2 (10.1 ± 3.8 cm H2O) or breath 3 (10.1 ± 2.8 cm H2O). In contrast, we
did not detect any significant independent effect of sleep stage
or any interaction between sleep stage and breath number on
Pcrit.
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In Figure 4, RN is illustrated for each sleep stage and breath number. ANOVA revealed a significant decrease in RN across breaths (p = 0.02). An overall decrease in RN from 25.6 ± 14.0 cm H2O to 20.2 ± 7.4 cm H2O/I/s was observed between the first and third breath. In contrast, we did not detect any significant independent effect of sleep stage or interaction between sleep stage and breath number on RN.
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No significant differences in either Pcrit or RN were found between sleep states. To determine why significant differences were not found, we examined how Pcrit and RN varied within patients between non-REM and REM sleep, by correlating the non-REM and REM values for these parameters (Table 2). Except for a significant breath-3 correlation in Pcrit between non-REM and REM sleep (p < 0.04), no significant correlations were observed between non-REM and REM Pcrit or RN values for breaths 1, 2, and 3. These findings suggests that state-related differences were not observed because the variability in these parameters between patients was considerable.
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EMGgg
In Figure 5, the tonic EMGgg is illustrated for sleep stage and breath number. ANOVA revealed a significant decrease in the tonic EMGgg in REM as compared with non-REM sleep (p < 0.001). No significant effect of breath number or interaction between breath number and sleep stage was detected. In Figure 6, the phasic EMGgg is illustrated for sleep stage and breath number. ANOVA revealed a significant decrease in the phasic EMGgg in REM as compared with non-REM sleep (p < 0.001), and a significant increase in the phasic EMGgg with breath number (p = 0.03). No significant interaction between breath number and sleep stage was detected, indicating that breath-by-breath recruitment of the phasic EMGgg did not differ between non-REM and REM sleep.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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In this study, we developed methods for examining the properties of the hypotonic upper airway during sleep in apneic patients. A state of relative hypotonia was induced by maintaining PN at increased levels so as to eliminate airflow obstruction and concomitant reflex activation of the pharyngeal musculature. PN was reduced repeatedly, and pressure-flow relationships for the upper airway were then analyzed for non-REM and REM sleep. We hypothesized that Pcrit would be highest in the first REM breath immediately after abruptly reducing PN. Instead, we found that significant increases in Pcrit occurred within three breaths after abrupt reductions in PN, and found no significant difference in Pcrit between non-REM and REM sleep. Moreover, these findings were not explained by alterations in EMGgg activity. When this EMG declined in REM sleep, Pcrit did not change, whereas increases rather than decreases in Pcrit occurred as EMG increased in breaths after a decrease in PN. Indeed, there was no consistent relationship between Pcrit and EMGgg across breaths and sleep stages. This finding suggested that mechanical rather than neural factors exert a major influence on Pcrit during periods of relative pharyngeal hypotonia in apneic patients.
Passive Pcrit and Neuromuscular Activity
The overall purpose of this study was to examine the relationship between Pcrit, sleep state, and breath number during periods of relative pharyngeal muscle hypotonia. This study evolved from a longstanding effort to establish whether increases in Pcrit in sleeping apneic patients (1, 3) were the result of structural alterations or disturbances in neuromuscular control. We recognized from previous studies in animals (5, 7) and postmortem infants (14) that Pcrit rises as neuromuscular activity wanes. In further studies in humans during complete neuromuscular blockade, Isono and colleagues found that Pcrit was higher in apneic patients than in normal subjects (19). They were able to attribute the increase in airway collapsibility in their apneic patients to an underlying structural defect, because neuromuscular activity had been abolished. Further studies are required to confirm this finding in well-characterized apneic patients and matched normal controls, but are hampered by the impossibility of routinely administering neuromuscular blocking agents to these subjects. To overcome this limitation, we explored physiologic approaches to measuring Pcrit during periods of relative pharyngeal-muscle hypotonia, in an effort to elucidate the structural basis for alterations in pharyngeal collapsibility.
Our methods for measuring a hypotonic Pcrit stemmed from an earlier study of the reflex control of Pcrit in the isolated feline upper airway (7). In this study, alterations in afferent activity from chemoreceptors and from lung and upper-airway mechanoreceptors were associated with significant changes in Pcrit, suggesting that reflexes played a major role in modulating pharyngeal collapsibility. We then suppressed all reflex activation of the pharyngeal musculature in this preparation, and found that Pcrit rose to levels observed during complete neuromuscular blockade. This finding in the isolated feline upper airway suggested that a hypotonic Pcrit could be determined in humans if reflex neuromuscular activation originating from chemoreceptors and from lung and upper-airway mechanoreceptors could be reduced.
Recent studies have also suggested that it is possible to suppress such reflex activation of the pharyngeal musculature in sleeping humans. These studies demonstrated dramatic reductions in pharyngeal neuromuscular activity when PN was increased in sleeping apneic patients (15, 18). This decrease could be attributed to alterations in afferent activity from chemoreceptor and from lung and airway mechanoreceptors caused by increases in ventilation, lung volume, and airway pressure, respectively, at increased levels of PN. Moreover, investigators recently found that pharyngeal neuromuscular activity remained quite low immediately after an abrupt reduction in PN during sleep (15). In the present study, we confirmed that reductions in phasic neuromuscular activity persisted after nasal pressure was decreased, and observed further decreases in tonic neuromuscular activity in REM as compared with non-REM sleep. Therefore, we have strong evidence that our methods minimized neuromuscular activity in the first breath after an abrupt decrease in PN, particularly during REM sleep.
When reflex pharyngeal neuromuscular activation from
chemo- (23) and mechanoreceptor (24) afferents was attenuated, an increase in pharyngeal collapsibility (Pcrit) had
been observed. Isono and coworkers further examined the
structural basis for alterations in pharyngeal properties by determining Pcrit from the relationship between pressure and
pharyngeal cross-sectional area in their apneic patients during
complete neuromuscular blockade (16). They found Pcrit to
be in the range of 0.9 to 2.8 cm H2O in their apneic patients after they had eliminated neuromuscular activity. We found
slightly lower Pcrit levels of 1.2 ± 3.9 cm H2O in the first
breath following abrupt reductions in PN. These differences in
Pcrit can be attributed to persistent neuromuscular activity in
our sleeping patients. When compared with markedly negative Pcrit values in waking humans with intact neuromuscular activity, however, the magnitude of this difference is rather small. We therefore suggest that our Pcrit measurements during periods of relative hypotonia largely reflected the influence of airway structures rather than neuromuscular activity
on pharyngeal collapsibility.
Mechanism for Breath-Related Changes in Airflow Dynamics
We recognize that our hypotonic Pcrit measurements may have been influenced by pharyngeal neuromuscular activity. After all, we found that phasic genioglossus muscle activity increased progressively from the first through the third breath, and that this activity was increased throughout all non-REM as compared with REM breaths. Although increased levels of genioglossus muscle activity have been associated with marked reductions in Pcrit (5, 6, 28), we observed no such relationship in our patients; rather the Pcrit increased significantly in subsequent breaths as neuromuscular activity rose during both non-REM and REM sleep. Nor did we find lower Pcrit levels in non-REM as compared with REM sleep. Thus, we failed to demonstrate any consistent relationship between Pcrit and genioglossus muscle activity, suggesting that the level of neuromuscular activity in pharyngeal dilators did not account for the variability that we observed in Pcrit.
What then might account for breath-to-breath increases in our hypotonic Pcrit? It is possible that this increase was caused by active constriction of the pharynx in response to sudden reduction of the nasal pressure. Although we did not monitor activity in the pharyngeal constrictors, it is known that these muscles activate primarily during expiration and are relatively quiescent in apneic patients during sleep, even after nasal pressure has been abruptly reduced for several breaths (29). Our Pcrit, however, was determined from measurements of inspiratory airflow, which were more likely to have been influenced by inspiratory than by expiratory patterns of muscle recruitment. Therefore, we believe it unlikely that expiratory recruitment of pharyngeal constrictors accounted for breath-to-breath increases in Pcrit in our patients.
Alternatively, breathwise increases in Pcrit in our study may have been due to mechanical rather than to neuromuscular factors. Mechanical changes may have resulted from lung deflation that occurred after PN was reduced. When the lung deflates, the trachea is known to move rostrally (30). Such rostral movement has been associated with increases in Pcrit and decreases in RN (31, 32), both of which have been attributed to reductions in longitudinal tension within the airway (32). In fact, similar responses in Pcrit and RN were demonstrated from the first through the third breath in our patients, which is consistent with rostral tracheal movement and reductions in longitudinal tension. Further evidence for decreases in longitudinal tension was provided by breath-to-breath measurements of Pes in our patients. Specifically, the end-expiratory Pes fell by 1.3 ± 0.9 cm H2O from the first to the third breath (p < 0.001) for runs in which the upper airway remained partially open (PN just exceeded Pcrit). This decrease suggests that end-expiratory lung volume fell by 130 to 260 ml (assuming a constant end-expiratory PN and a lung compliance of 100 to 200 ml/cm H2O). As end-expiratory lung volume fell, therefore, rostral tracheal movement may have decreased longitudinal airway tension, a change that could account for the breath-to-breath increases in Pcrit and decreases in RN that we observed.
The breath-to-breath increases that we observed in Pcrit may also have been due to hysteresis in the pharyngeal Pcrit. This hysteresis is characterized by an increase in the pharyngeal critical opening pressure relative to its critical closing pressure (13, 33, 34). Such hysteresis implies that the pharynx may not have completely reopened once collapse occurred. We recognize that the pharynx collapsed in our patients during the first flow-limited inspiration after a decrease in PN. Thereafter, a higher opening pressure may have prevented recovery of patency during expiration, leaving the pharynx even more prone to collapse (higher Pcrit) during the subsequent flow-limited inspiration. Thus, hysteresis in Pcrit may have also been responsible for breath-to-breath increases in Pcrit after abrupt reductions in PN.
Implications
The considerations we have described lead us to conclude that mechanical factors predominate in the modulation of Pcrit during periods of relative hypotonia. We found that the pharynx became more collapsible (increased Pcrit) with subsequent breaths after the first following an abrupt decrease in PN, despite progressive increases in genioglossus muscle activity. Recruitment of this dilator should have decreased Pcrit, thereby offsetting observed increases in Pcrit resulting from alterations in airway longitudinal and/or surface tension. Therefore, our methods may have underestimated the influence of mechanical factors leading to an increase in Pcrit following reductions in PN. Alternatively, the finding that the Pcrit hypotonic did not change despite substantial reductions in genioglossus muscle activity in REM sleep suggests that neuromuscular activity had little influence on our Pcrit measurements. Taken together, the findings in the present study suggest that mechanical factors dynamically modulate the structural properties of the upper airway. Further studies are required to delineate how specific structural influence airway collapsibility when neuromuscular activity is held constant.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Alan R. Schwartz, Johns Hopkins Sleep Disorders Center, Division of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224.
(Received in original form June 17, 1997 and in revised form November 5, 1997).
Acknowledgments: The authors wish to acknowledge Mr. Eugene Scarberry of Respironics, Inc., for providing technical assistance and components for regulating nasal pressure in this study.
Supported by Grants HL503810 and HL37379 from the National Heart, Lung and Blood Institute.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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