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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We determined whether upper airway obstruction in normal individuals with intact reflexes could produce the syndrome of obstructive sleep apnea. Upper airway obstruction was produced in
12 normal individuals by lowering nasal pressure to 
10 cm H2O
during sleep. Full night polysomnography was performed during
two consecutive nights of sleep with subatmospheric nasal pressure and compared with control nights before and after the negative pressure nights. We found that the application of negative
pressure was associated with the development of recurrent obstructive apneas (non-REM-disordered breathing rate, 32.6 ± 34.8 and 37.8 ± 29.1 events/h during each of two negative pressure
nights; p < 0.001) that were associated with oxyhemoglobin desaturation, arousals from sleep, and alterations in sleep stage distribution. Moreover, the median daytime sleep latency after two
nights of sleep with subatmospheric pressure fell from 6.9 ± 1.1 to
3.4 ± 0.6 min, and rose significantly again to 8.1 ± 1.5 min (p < 0.03) after the control night following subatmospheric pressure
nights. Our findings suggest that a decrease in the pharyngeal
transmural pressure alone is a sufficient condition for the production of the sleep apnea syndrome in normal individuals.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Obstructive sleep apnea (OSA) is characterized by periods of recurrent upper airway obstruction during sleep (1, 2). It is well recognized that airflow obstruction is due to collapse of the upper airway. Although the mechanism for upper airway collapse is not clear, it is known that apneas are abolished when collapse is relieved with nasal continuous positive airway pressure (CPAP) (3) or bypassed with tracheostomy (4, 5). Thus, current evidence indicates that collapse of the upper airway plays a primary role in the pathogenesis of OSA.
Previous investigators have attempted to model the factors contributing to the development of sleep-disordered breathing (6). In addition to upper airway obstruction, they have postulated that chemoreflex and arousal mechanisms also play a role (7). It is possible that a defect in one or more of these reflex responses may be contributory. Alternatively, these reflex responses may be normal in patients with OSA, and increased collapsibility of the upper airway alone can produce the syndrome. The purpose of the present study is to determine whether upper airway obstruction alone in normal individuals with intact reflexes produces the syndrome of OSA.
In previous studies, we demonstrated that it was possible to
collapse and obstruct the upper airway in normal individuals by lowering nasal pressure progressively during sleep. Our
findings led us to postulate that the upper airway in normal
sleeping individuals functioned as a collapsible conduit (11-
15). Its patency was determined by its transmural pressure
namely, the difference between pressure within the airway lumen and the pressure exerted by tissues surrounding the site
of collapse. Normal individuals maintained a positive pharyngeal transmural pressure of approximately 0 to +10 mm Hg
during sleep. In contrast, upper airway obstruction in apneics
was associated with development of negative transmural pressure during sleep. We, therefore, applied 10 cm H2O to normal subjects to produce a negative transmural pressure during
sleep. During the application of 10 cm H2O, we examined
the response in standard polysomnographic measures of apnea severity, sleep structure, and daytime somnolence. The results indicate that OSA can be induced by obstruction of the
upper airway during sleep, even in individuals with presumably normal reflex and arousal responses.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject Selection
Twelve subjects recruited from the community were studied. Each subject was free of any significant medical illness, sleep complaints, or nasal symptoms. Informed consent was obtained from each subject for this protocol, which had been approved by the Human Investigation Review Board of our institution. A baseline polysomnogram was performed in each subject as well as multiple sleep latency testing to rule out the presence of sleep apnea as defined by standard techniques previously described (16).
Polysomnography
Standard polysomnographic techniques (17) were used to categorize subject sleep architecture and are outlined as follows: left and right electrooculograms, a submental electrode, and surface electroencephalographic electrodes placed at C3-A2, and C3-O1 were used to stage sleep. A digital pulse oximeter (model 114, BTI, Biox III; Biox Oximetry Technology, Boulder, CO) was used to record arterial hemoglobin saturation (SaO2). A continuous electrocardiogram recorded heart rate and rhythm. Airflow was monitored with a pneumotachometer attached to the nasal circuit, and respiratory effort was monitored with an esophageal balloon that was placed according to standard techniques. A polygraph (model 780; Grass Instruments, Quincy, MA) ran continuously at 10 mm/s to record all physiologic data throughout the night. Nocturnal sleep studies were performed between 10:30 P.M. and 8:00 A.M. Multiple daytime sleep latency tests were performed according to standard protocol (18) at 9:00 A.M., 11:00 A.M., 1:00 P.M., and 3:00 P.M. the day after the control nights 1 and 4 and after negative pressure night 3 (see PROTOCOL, below).
Breathing Circuit and Respiratory Monitoring
A vacuum source with a voltage regulator was attached to the inspiratory circuit to apply continuous negative pressure to the nasal mask (for details, see Figure 1 in Reference 13). A 200-L capacitance reservoir was placed at the inflow port to maintain the level of subatmospheric nasal pressure applied to the mask nearly constant throughout the respiratory cycle. A fixed leak was interposed between the pneumotachograph and the nasal mask to permit ambient air to enter the circuit while negative pressure applied to the nasal mask was obtained. Inspiratory and expiratory airflow was measured with a pneumotachometer (Hans Rudolph, Kansas City, MO) connected in series with the breathing circuit. Nasal pressure was monitored continuously through a port in the nasal mask with a Statham differential pressure transducer (model 13436; Gould Statham, Oxnard, CA) referenced to atmospheric pressure. Respiratory effort was monitored either with an esophageal balloon or thoracic and abdominal strain gauges. A 10-cm Hyatt-type esophageal balloon was placed 10 cm above the gastroesophageal junction. Esophageal pressure was measured with a Gould Statham pressure transducer (P 23; Gould Instruments, Cleveland, OH).
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Protocol
Each subject had baseline polysomnography performed 1 wk before and 1 wk after negative pressure intervention nights. Multiple sleep latency testing was also performed the day after both baseline studies. During each baseline nocturnal study, subjects slept with a nasal CPAP mask that was connected to a pneumotachometer, which was left open to atmosphere.
Patients also slept for two nights with subatmospheric pressure applied to a nasal mask. On these two nights, the subjects were allowed
to initiate sleep while 2 cm H2O nasal pressure was applied continuously to prevent rebreathing air in the breathing circuit. After the subjects demonstrated Stage II sleep, the nasal pressure was gradually
lowered stepwise every 5-10 min by 2-cm H2O increments until a
level of 10 cm H2O was achieved. With the occurrence of a sustained arousal, the level of pressure applied to the nasal mask was increased toward 2 cm H2O. Subjects were then allowed to reinitiate
sleep, after which 10 cm H2O nasal pressure was again applied. Multiple sleep latency testing was performed the day after the second
night of negative nasal pressure.
Sleep Architecture and Daytime Sleep Latency Testing
Sleep staging was performed on the basis of criteria established by Rechtschaffen and Kales (17). For nocturnal polysomnograms, the total sleep time, and aggregate time spent in Stages I and II combined, slow wave sleep, and REM sleep were calculated. For the daytime sleep latency tests, the time to sleep onset (Stage I sleep) was determined, and the median latency for four naps was reported.
Respiratory Analyses
Disordered breathing events were classified as apnea when airflow
had ceased for 
5 s, and hypopnea when a 50% or greater reduction
in airflow occurred that was accompanied by either an arousal from
sleep or 4% oxyhemoglobin desaturation. The duration of each disordered breathing episode was measured from end expiration of the
breath preceding the disordered breathing event to the start of a normal expiration following the disordered event. Disordered breathing
events were classified as central events when there was absence of
airflow and respiratory fluctuation in esophageal pressure and/or excursions of the thoracic and abdominal strain gauges. The event was
classified as obstructive when there was cessation of airflow despite
continued respiratory swings in esophageal pressure and/or excursions in thoracic and abdominal strain gauges. Mixed events were defined as having components of both obstructive and central features.
The following parameters were calculated. The disordered breathing rate (DBR) consisted of the total number of disordered breathing
events divided by the total time spent asleep at 10 cm H2O nasal
pressure. The proportion of total disordered breathing time during
which airflow ceased (complete upper airway obstruction or apnea
was present) was also calculated (apnea time/disordered breathing
time). The baseline arterial oxyhemoglobin saturation and low arterial hemoglobin saturation accompanying each disordered breathing
event were reported. The frequency with which the disordered breathing events were terminated with arousals was also reported.
Statistical Analyses
Analysis of variance (ANOVA) was used to detect significant differences in outcome variables between nights, using Crunch 4 software (Crunch Software, Oakland, CA). Two-factor ANOVA was used to detect significant differences in sleep architecture, disordered breathing rate, apnea time/disordered breathing time, arterial hemoglobin desaturation, and apnea duration between factors of night and sex. When sex-related differences were not detected, the data for men and women were pooled for subsequent analyses. If the ANOVAs were significant, a Newman-Keuls test was used to identify which means were significantly different. A p < 0.05 level of significance was used, and data are reported as means ± SE unless otherwise stated.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Anthropomorphic Data
The age, sex, height, weight, and body mass index (BMI) for each of the 12 subjects who participated in the study are shown in Table 1. The BMI (range, 19.0-26.9 kg/m2) and age (range, 19-45 yr) were both matched between sexes. All female subjects were premenopausal, and only one subject (subject 11) was noted to have enlarged tonsils.
Sleep Architecture
In Figure 1, sleep architecture is illustrated for control nights 1 and 4 and negative pressure nights 2 and 3. No significant differences were detected between men and women by ANOVA
in total sleep time, or in time spent in Stages I and II, slow
wave, or REM sleep. For the entire group, the mean total
sleep time (Figure 1, top) was 384 ± 17 and 409 ± 13 min on
control nights 1 and 4, and fell to 322 ± 25 min on the first
night of negative pressure (p < 0.02). There was a subsequent
increase in total sleep time to 386 ± 16 min on the second
night of negative pressure (p < 0.01), which was not different
from either the pre- or postnegative pressure control nights.
The time spent asleep at 10 cm H2O increased from 261 ± 25 min on night 2 to 335 ± 17 min on night 3.
During the two nights of negative pressure, we also found that Stage I/II sleep rose (p < 0.02), slow wave sleep decreased (p < 0.01), and REM sleep decreased (p < 0.0002) compared with control nights 1 and 4. We also compared negative pressure nights 2 and 3 and found that slow wave sleep increased (p < 0.03) and REM sleep increased (p < 0.03) on night 3.
Respiratory Responses
A sample recording illustrating the respiratory and polysomnographic responses of one subject breathing with 10 cm
H2O nasal pressure during non-REM sleep is illustrated in
Figure 2. Here, recurrent obstructive apneas with oxyhemoglobin desaturation and progressive increases in esophageal
pressure swings can be seen. These disordered breathing episodes were terminated by arousals.
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= airflow;
PES = esophageal pressure.
In Figure 3, the non-REM disordered breathing rate is illustrated for each night for both men and women. Although a trend existed for men to have a higher DBR than women, there was no significant difference. In one female subject with enlarged tonsils (subject 11), the DBR was 94 and 60 episodes/h in negative pressure nights 2 and 3, respectively. When this subject was excluded, the DBR in women was 12.9 ± 0.9 versus 46.0 ± 5.2 events/h in men (p = 0.053) for the mean of negative pressure nights 2 and 3. After pooling DBR for men and women, we found that DBR increased from 0.4 ± 0.3 to 32.6 ± 10.0 and 37.8 ± 8.4 on nights 1 through 3, respectively (p < 0.001), and fell again to 0.0 ± 0.1 on night 4 (p < 0.001).
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During REM sleep, the total number of disordered breathing events was 0.3 ± 0.1 and 0.5 ± 0.4 on control nights 1 and 4. With the application of negative pressure, REM sleep time was substantially reduced (Figure 1) and consequently a total of only 4.1 ± 2.7 and 10.7 ± 3.3 disordered breathing events occurred on negative pressure nights 2 and 3, respectively (mean data for men and women combined).
In Figure 4, disordered breathing event duration is illustrated for negative pressure nights 2 and 3. Events lasted 18.6 ± 1.6 and 18.5 ± 1.2 s, respectively, for men and women combined. No significant difference was noted between negative pressure nights or between men and women.
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Arterial oxyhemoglobin desaturations are illustrated in Figure 5 for men and women on each negative pressure night. Non-REM disordered breathing episodes were associated with a significant fall (p < 0.01) in SaO2 that was not different between nights 2 and 3, but was greater (p < 0.03) in men (5.1 ± 1.1%) than women (2.0 ± 0.3%).
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The characteristics of the disordered breathing episodes are shown in Figure 6 for negative pressure nights 2 and 3 in men and women. Disordered breathing episodes were predominantly obstructive in both groups for each night. The apnea time to disordered breathing time (AT/DBT) was greater in men than women (65.4 ± 10.1 versus 26.8 ± 11.2%, p < 0.02), indicating that apneas predominated in the men whereas hypopneas predominated in women. The majority of disordered breathing episodes were associated with arousals in both groups on both nights.
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Relationship between BMI and the Disordered Breathing Rate
Despite a relatively narrow BMI range among our subjects,
the DBR data during non-REM sleep and BMI were significantly correlated [regression equation: DBR (events/h) = 7.2 × BMI (kg/m2) 124.5; r = 0.77, p < 0.01] for the men on
negative pressure nights 2 and 3. In contrast, no such significant correlation was observed in the women, regardless of
whether subject 11 was included or excluded.
MSLT
The median sleep latency test (MSLT) results are shown in Figure 7 and there was no difference between men and women. Combining the results for men and women, we found a decrease (p < 0.03) in MSLT after negative pressure night 3 (3.4 ± 0.5 min) compared to control night 4 (8.1 ± 1.5 min), but not in comparison with control night 1 (6.9 ± 1.1 min).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we examined the effect of continuous subatmospheric nasal pressure on breathing patterns in normal individuals during sleep. Normal individuals were studied because they were presumed to have no known disturbances in reflex responses to upper airway obstruction induced by subatmospheric pressure. We found that normal individuals subjected to subatmospheric nasal pressure throughout the night exhibit recurrent, predominantly obstructive apneas and hypopneas. The apneas observed in our normal individuals were similar in characteristics to those seen in patients with obstructive sleep apnea in both their frequency and duration (19). Moreover, they were associated with oxyhemoglobin desaturation, frequent arousals from sleep, and alterations in sleep stage distribution. Although total sleep time was not altered by the application of subatmospheric pressure, our subjects exhibited significant reductions in slow wave and REM sleep and in daytime sleep latency, consistent with the development of subjective daytime hypersomnolence. Thus, subatmospheric pressure produced both the clinical and polysomnographic features of the obstructive sleep apnea syndrome. Our findings suggest that the sleep apnea syndrome could be primarily due to the development of upper airway obstruction rather than to abnormalities in reflex or arousal responses.
With the application of continuous subatmospheric nasal
pressure, obstructive apneas alternated with periods of arousal
from sleep. During sleep, subatmospheric pressure produced
pharyngeal obstruction by lowering the transmural pressure
below zero (Figure 8, Pathway A: Pn decreases from zero to
10 cm H2O) (13). In fact, complete upper airway obstruction
occurs spontaneously in patients with apnea because the pharyngeal transmural pressure becomes negative during sleep
(15). In contrast, upper airway patency was restored during
arousal, indicating that the upper airway transmural pressure
became positive (Figure 8, Pathway B: Pn = 10 cm H2O,
asleep versus awake). Transmural pressure became positive in
the presence of a continuous negative intraluminal pressure
because the pressure surrounding the site of pharyngeal collapse (Psurr) fell below the level of subatmospheric intraluminal pressure. The fall in pressure surrounding the airway can
be attributed to activation of upper airway muscles (20) that
dilate and elongate the upper airway (1, 21). Although upper airway neuromuscular activity was not measured, such activation is well recognized to occur during microarousals in patients with obstructive sleep apnea (1). These arousals are
thought to be triggered by reflexes associated with alterations
in blood gases and breathing mechanics (7, 24, 25). It
should be noted that the reflex and arousal responses to airway obstruction in our normal individuals appear comparable
to those in patients with apnea, indicating that such a defect
may not be required to produce obstructive sleep apnea. It is
still possible that defects in reflex responses to airway obstruction influence the periodicity of apneic episodes in patients with this disorder. Nevertheless, our findings suggest that upper airway obstruction is both a necessary and sufficient condition to produce obstructive sleep apnea.
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In theory, several distinct responses were possible during the application of subatmospheric pressure. First, our subjects might have awakened from sleep in response to airway obstruction, and failed to reinitiate sleep thereafter. Second, airway obstruction may have activated one of several respiratory reflexes that enable the upper airway to remain patent before arousing subjects from sleep. If such reflexes improved pharyngeal patency and augmented ventilation, the apnea-hypopnea index would have been minimal and either steady state snoring or normal breathing would have ensued during sleep. In fact, this breathing pattern is commonly observed in children with sleep-disordered breathing (26). Third, as we observed, airway obstruction produced transient arousals from sleep, leading to the development of recurrent obstructive apneas each time the subjects reinitiated sleep (27). It is possible that the presence of normal reflex and arousal responses to upper airway obstruction in our subjects produced by subatmospheric pressure may have diminished the clinical severity of obstructive sleep apnea that we observed. Nevertheless, our findings suggest that the development of upper airway obstruction per se can play a primary role in the pathogenesis of obstructive sleep apnea.
Despite the induction of repeated apneas in all our normal subjects, apnea periodicity was variable, especially in men, who exhibited greater apnea-hypopnea indices than all but one of our women. Although the reason for sex-related differences is not immediately apparent, our results are consistent with epidemiological data suggesting a higher prevalence of sleep-disordered breathing in men than women (28). In our study, it is possible that differences may have been due to alterations in the pressure surrounding the site of pharyngeal collapse. If the surrounding pressure in men were higher (less subatmospheric) than in women, greater degrees of upper airway obstruction would have occurred when negative pressure was applied. In fact, we found that the ratio of apneic to hypopneic episodes was greater in the men, indicating a higher degree of obstruction. Furthermore, we found that the apnea- hypopnea index correlated with the body mass index in the men, but not in the women. These findings suggest that weight may have accounted for some of the variability observed in apnea severity in men, but might not exert a comparable influence in women of normal weight (28). Although the physiologic basis for this correlation is unclear, we have previously demonstrated that weight loss increases the upper airway transmural pressure during sleep (decreased collapsibility) (29). We therefore suggest that variability in apnea severity in the present study may be attributable to both sex- and weight- related differences among our normal subjects.
In summary, our findings indicate that clinically significant
levels of obstructive sleep apnea could be produced when a nasal pressure of 10 cm H2O is applied to normal subjects during sleep. We determined that this level of subatmospheric
pressure was sufficient to produce pharyngeal airflow obstruction, suggesting that the development of a negative pharyngeal
transmural pressure played a primary role in the pathogenesis
of obstructive sleep apnea. It is possible that our subjects
might have exhibited an even greater degree of obstructive
sleep apnea if the pharyngeal transmural pressure had been
made more negative by applying greater amounts of subatmospheric nasal pressure. Our findings in normal subjects suggest
that a disturbance in reflex responses is not necessary for the
development of recurrent obstructive apneas. Rather, structural or neuromuscular factors that decrease the pharyngeal
transmural pressure will predispose to this disorder.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Alan R. Schwartz, M.D., Johns Hopkins Sleep Disorders Center, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: schwartz{at}welchlink.welch.jhu.edu
(Received in original form April 26, 1999 and in revised form November 12, 1999).
Acknowledgments: Supported by National Institutes of Health Grants HL 37379 and HL 50381.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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J. Black Pro: Modafinil Has a Role in Management of Sleep Apnea Am. J. Respir. Crit. Care Med., January 15, 2003; 167(2): 105 - 106. [Full Text] [PDF]
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M. J. TOBIN Sleep-disordered Breathing, Control of Breathing, Respiratory Muscles, Pulmonary Function Testing, Nitric Oxide, and Bronchoscopy in AJRCCM 2000 Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1362 - 1375. [Full Text] [PDF]
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D. Stanescu, C. Veriter, and A. R. Schwartz A MODEL OF OBSTRUCTIVE SLEEP APNEA IN NORMAL HUMANS Am. J. Respir. Crit. Care Med., March 15, 2001; 163(4): 1031 - 1031. [Full Text]
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