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J Appl Physiol 97: 98-108, 2004. First published February 27, 2004; doi:10.1152/japplphysiol.00462.2003
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Developmental changes in upper airway dynamics

Carole L. Marcus,1 Lucila B. Fernandes Do Prado,2 Janita Lutz,1 Eliot S. Katz,1 Cheryl A. Black,1 Patricia Galster,1 and Kathryn A. Carson3

1The Eudowood Division of Pediatric Respiratory Sciences and the 3Division of Oncology Biostatistics, Johns Hopkins University, Baltimore, Maryland 21287-2533; and 2Department of Neurology and Internal Medicine, Universidade Federal de São Paulo-Escola Paulista de Medicina, São Paulo, Brazil

Submitted 2 May 2003 ; accepted in final form 17 February 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Normal children have a less collapsible upper airway in response to subatmospheric pressure administration (PNEG) during sleep than normal adults do, and this upper airway response appears to be modulated by the central ventilatory drive. Children have a greater ventilatory drive than adults. We, therefore, hypothesized that children have increased neuromotor activation of their pharyngeal airway during sleep compared with adults. As infants have few obstructive apneas during sleep, we hypothesized that infants would have an upper airway that was resistant to collapse. We, therefore, compared the upper airway pressure-flow () relationship during sleep between normal infants, prepubertal children, and adults. We evaluated the upper airway response to 1) intermittent, acute PNEG (infants, children, and adults), and 2) hypercapnia (children and adults). We found that adults had a more collapsible upper airway during sleep than either infants or children. The children exhibited a vigorous response to both PNEG and hypercapnia during sleep (P < 0.01), whereas adults had no significant change. Infants had an airway that was resistant to collapse and showed a very rapid response to PNEG. We conclude that the upper airway is resistant to collapse during sleep in infants and children. Normal children have preservation of upper airway responses to PNEG and hypercapnia during sleep, whereas responses are diminished in adults. Infants appear to have a different pattern of upper airway activation than older children. We speculate that the pharyngeal airway responses present in normal children are a compensatory response for a relatively narrow upper airway.

sleep-disordered breathing; critical pressure; infants; children; upper airway collapsibility

NORMAL CHILDREN ARE LESS LIKELY to snore than normal adults and rarely have any obstructive apneas during sleep (33). Consistent with this clinical finding, our laboratory (30) recently showed that the upper airway of normal children is less susceptible to collapse than that of adults. This could be due to structural differences in the upper airway or to functional differences in neuromotor tone.

In our laboratory's previous study (30), we found that upper airway collapsibility during sleep was modulated by the central ventilatory drive. The upper airway muscles are accessory muscles of respiration and, as such, are activated in response to increases in the central ventilatory drive (57). Children are known to have a higher ventilatory drive than adults (28); thus it is possible that they have increased activation of their upper airway muscles in response to differing stimuli. We, therefore, hypothesized that normal children have increased neuromotor activation of the pharyngeal airway compared with adults, resulting in a more patent upper airway.

Little is known about upper airway collapsibility and upper airway dynamic function in infants compared with older children and adults. We, therefore, included infants in this study. As infants have few obstructive apneas during sleep (23), we hypothesized that infants would have an upper airway that was resistant to collapse.

To test these hypotheses, dynamic upper airway responses were measured during sleep across the age span, from infancy through adulthood. Responses were tested in several ways. It has been shown that upper airway neuromotor activity is suppressed by continuous positive airway pressure (CPAP), resulting in relative hypotonia (56). In contrast, the upper airway is activated by the administration of subatmospheric pressure. This activation is not instantaneous but takes at least three breaths to develop (26, 47). Thus acutely dropping nasal pressure (PN) from a positive level to a subatmospheric level for several breaths results in a relatively hypotonic upper airway, whereas maintaining subatmospheric pressure for longer periods of time results in activation of the airway. Therefore, in the present study, upper airway responses were tested by using both brief and prolonged applications of subatmospheric pressure. In addition, upper airway responses were tested in some of the children and adults by administering carbon dioxide during sleep.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Upper airway, dynamic pressure-flow () responses (PFR) during sleep were compared among normal, nonsnoring, nonobese infants, children, and adults. Children and adults first underwent baseline polysomnography on a separate night. As normal infants have a very low incidence of obstructive sleep apnea (23), their baseline data were obtained during the second half of the night after the PFR measurements were obtained, rather than during a separate night.

Study Group

The study group consisted of 1) infants, 2) children, and 3) adults. The children were the same as those used for a simultaneous study evaluating upper airway responses in children with the obstructive sleep apnea syndrome (C. L. Marcus, J. Lutz, E. S. Katz, C. A. Black, P. Galster, and K. A. Carson, unpublished observations). Subjects were recruited from the community by means of advertisements. Subjects with habitual (nightly) snoring or other symptoms of apnea were excluded. All controls were nonobese, defined as weight <120% of the ideal weight for height for infants (25); body mass index <95% predicted for age, height, and race for children (43); and body mass index <30 kg/m2 for adults (35). Infants were defined as being ≤1 yr of age. Infants with a history of prematurity, apparent life-threatening events, gastroesophageal reflux, or a family history of sudden infant death syndrome were excluded. The child group consisted of prepubertal school-aged children who were old enough to cooperate with testing (i.e., 5–13 yr of age). Children with a history of tonsillectomy and/or adenoidectomy were excluded, as the obstructive sleep apnea syndrome is now a common indication for adenotonsillectomy (42). Because tonsillectomies and adenoidectomies were performed so commonly in the past, this exclusion criterion was not applied to the adult group (aged ≥21 yr).

Written, informed consent was obtained from each subject or the parents or legal guardians. In addition, assent was obtained from children older than 5 yr of age. The study was approved by the Institutional Review Board of Johns Hopkins University, and studies were performed according to the Declaration of Helsinki.

Baseline Polysomnography

Polysomnographic studies were performed overnight. During polysomnography, the following parameters were measured and recorded continuously by using a computerized polysomnography system (Alice 3, Healthdyne, Marietta, GA): electroencephalogram (C3/A2, O1/A2); right and left electrooculogram; submental electromyogram (EMG); tibial EMG; electrocardiogram; chest and abdominal wall motion (piezoelectric transducers or respiratory inductance plethysmography); oronasal (3-pronged thermistor); end-tidal PCO2 (PETCO2), measured at the nose by infrared capnometry (Nellcor N-1000, Van Nuys, CA); arterial oxygen saturation (SaO2) by pulse oximetry (Nellcor N-1000); and oximeter pulse waveform. Subjects were also monitored and recorded on videotape, by using an infrared video camera, and were continuously observed by a polysomnography technician. Sleep architecture and arousals from sleep were analyzed by using standard techniques (3, 5, 40). Cardiorespiratory parameters were scored by using pediatric standards; i.e., obstructive apneas of any length were scored (2). Hypopneas were scored if there was a qualitative decrease in oronasal ≥50%, associated with a change in the PETCO2 waveform, paradoxical breathing and desaturation ≥3%, and/or arousal (6).

Measurement of PFR

PFR were obtained during a separate, overnight polysomnogram (except for the infants, who were studied on the same night), by using modifications of previously described techniques (8, 30). Upper airway dynamics were measured under three conditions, in random order: 1) stepwise, decremental, steady-state decreases in PN, which was hypothesized to result in sequential activation of the upper airway ("gradual" technique); 2) acute, transient, intermittent drops in PN from a baseline holding pressure, which was hypothesized to result in a relatively hypotonic airway ("intermittent" technique); and 3) decremental decreases in PN during CO2 breathing. CO2 challenges were performed in the first 10 children and adults studied.

During PFR, routine polysomnographic parameters were measured as described previously. In addition, the subject breathed through a CPAP gel mask (Respironics, Pittsburgh, PA) attached to a heated pneumotachometer (Hans Rudolph, Kansas City, MO) and transducer (Validyne Engineering, Northridge, CA). PN was measured within the mask by using a differential pressure transducer referenced to atmosphere. PETCO2 was measured via a port on the mask by using an infrared capnometer (Ametek, Paoli, PA). Transcutaneous PCO2 was also measured (Radiometer, Paramus, NJ). A thermistor was placed at the mouth to detect oral breathing. Pressure and signals, in addition to selected other polysomnographic channels, were acquired by using DATAQ Instruments (Akron, OH) hardware and WinDaq software and were simultaneously displayed on the Alice system. PN was altered in either a positive or negative (subatmospheric) direction by using a device consisting of dual CPAP machines, one of which was modified by Respironics to provide subatmospheric pressure. A toggle switch allowed the subject to be switched rapidly between positive and negative pressure. The equipment was capable of delivering PN over a range of +22 to –22 cmH2O.

In infants, measurements were performed during quiet sleep (3). In children and adults, measurements were performed during non-rapid eye movement sleep, preferentially during slow-wave sleep. When measurements during slow-wave sleep were not possible (due to sleep stage transitions or lack of deep sleep in the instrumented, laboratory situation), measurements were performed during stage 2 sleep. Our laboratory has previously shown that PFR does not differ between stage 2 and slow-wave sleep (30). Pilot experiments attempting to obtain measurements during rapid eye movement sleep were unsuccessful due to arousal.

Gradual technique.   Subjects were placed on a level of CPAP sufficient to abolish inspiratory limitation (generally 2–4 cmH2O). Inspiratory limitation was considered to occur when failed to increase, despite increasing respiratory effort, as demonstrated by the characteristic waveform. The characteristic waveform pattern consisted of increasing inspiratory followed by a midinspiratory plateau (11, 32). Once inspiratory limitation had occurred, PN was lowered in 2-cmH2O steplike decrements every 30 s until approached zero or an arousal occurred (Fig. 1).



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  		Fig. 1. Techniques for lowering nasal pressure (PN) for the gradual and intermittent techniques are shown.

 
Intermittent technique.   Subjects were placed on a CPAP level sufficient to abolish inspiratory limitation (the holding pressure). PN was then decreased abruptly by 2 cmH2O for three to five breaths, after which it was rapidly returned to the holding pressure. PN was dropped repeatedly to incrementally lower levels, with a return each time to the holding pressure, until either approached zero or arousal occurred (Figs. 1 and 2). Data from the first three breaths were analyzed.



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  		Fig. 2. PN and flow () tracings are shown from a child during the intermittent technique. Decreasing PN (arrow) results in diminished . Breaths 1–3 have small values with a -limited pattern. Breaths 4 and 5 are larger and show a transition to a non--limited pattern, suggesting that activation of the upper airway is occurring at that point.

 
Genioglossal EMG measurements during gradual and intermittent PFR were performed in five additional children during sleep by using an intraoral mouthpiece, as previously described (24).

CO2 responses.   CO2 responses were performed while using the gradual technique. Subjects were placed on a CPAP level sufficient to abolish inspiratory limitation. CO2 was then introduced via a fine nasal cannula beneath the mask, sufficient to raise the transcutaneous PCO2 by 3 Torr. The gel mask was able to make a seal around the cannula. In general, 0.4 l/min of 100% CO2, blended with the through the CPAP circuit, were required. This relatively mild degree of hypercapnia was chosen as larger amounts of CO2, combined with the subatmospheric PN, resulted in prompt arousal. Transcutaneous PCO2 was measured rather than PETCO2, as the end-tidal waveform was lost during the administration of negative pressure. The response time of the transcutaneous CO2 electrode to a step change increase in CO2 was 35 s. The median time for the transcutaneous PCO2 monitor to reach the goal of 3 mmHg above baseline was 91 s. Following 3 min of baseline CO2 administration, PN was decreased in a steplike fashion until approached zero or an arousal occurred. CO2 administration was continued throughout the challenge.

Data Analysis

The average midinspiratory was taken from the lowest two consecutive breaths at each level of pressure. Pressure- curves were constructed by plotting maximal inspiratory (Imax) of -limited breaths against PN. PN vs. curves were fitted by least squares linear regression. The critical closing pressure (Pcrit) was defined as the x-axis intercept of the regression line (Imax = 0). Consistent with previous studies (30), many of the normal children in the present study did not have decreases in Imax, even at markedly subatmospheric pressures (Fig. 3). In these cases, the x-intercept could not be determined without extreme extrapolation, and, consequently, Pcrit could not always be determined. Therefore, the slope of the upstream pressure- curve was also used to characterize the upper airway response (30). As our equipment allowed us to apply a maximum negative pressure of –22 cmH2O, we arbitrarily elected to assign a threshold value of –25 cmH2O to Pcrit data that were extrapolated to less than –25 cmH2O. This allowed us to apply statistical methods to the Pcrit data. Note that Fig. 4 shows the raw Pcrit data without the arbitrary cutoff.



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  		Fig. 3. Typical example of pressure- relationships by using the gradual ({bullet}) vs. intermittent ({circ}) techniques in a child is shown. The intermittent technique results in a more collapsible upper airway, with a steeper slope and a higher critical closing pressure. Imax, maximal inspiratory .

 


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  		Fig. 4. Median group pressure- data for the gradual (solid line) vs. intermittent (dotted line) techniques are shown for all subjects in whom paired data were available. Note that the figures show the raw critical closing pressure data without the arbitrary cutoff of –25 cmH2O. See text for P values. N, no. of subjects.

 
Statistical Analysis

Nonparametric methods were used as most data were not normally distributed. All results are expressed as median (range), unless otherwise specified. Differences were compared between groups by using the Kruskal-Wallis test. If the Kruskal-Wallis test was significant for the three groups, then pairwise group comparisons were performed. Differences between conditions for the same individual were compared by using the Wilcoxon signed-rank test. The mean difference in inspiratory between individual breaths as a percentage of baseline during the intermittent challenges was calculated for each patient and analyzed by using the Wilcoxon signed-rank test.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Study Population

Sixty-one subjects were recruited. Three adults and four infants did not sleep well enough to allow for meaningful PFR measurements, one child was excluded due to an abnormal baseline sleep study showing obstructive apnea, and one infant was excluded due to a history of central apnea associated with a respiratory syncytial virus infection. Thus 52 subjects competed the study: 17 infants, 22 children, and 13 adults. Of these, not all slept well enough to allow for all parts of the protocol to be performed. All subjects successfully completed the gradual responses. Intermittent responses were performed in 14 infants, 20 children, and 11 adults. CO2 responses were tested in the first 10 children and 10 adults.

Subject demographics and baseline polysomnographic results are shown in Table 1.


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  		Table 1. Study group

 
Gradual and Intermittent Pressure- Measurements

Our laboratory (30) has previously shown that normal children have a much less collapsible upper airway in the activated state than adults. This resulted in a very flat slope, such that Pcrit could not be determined without extreme extrapolation (30). We had similar findings in the present study using the gradual technique, with only 30% of the children having a determinable Pcrit (i.e., Pcrit greater than –25 cmH2O). Indeed, a few children had such a flat PFR that there was actually a slightly negative tilt to the slope. However, the intermittent technique resulted in a steep slope in the children, in contrast to the flat slope seen with the gradual technique (Figs. 3 and 4). This resulted in a measurable Pcrit that fell within the range of PN deliverable by our equipment in 50% of the children. We, therefore, chose to use the intermittent technique as the baseline to which other conditions could be compared.

The nasal holding pressure, the first PN at which virtually all breaths for that run were -limited (i.e., the PN at which data began to be collected for each run) and the lowest PN are shown in Table 2. Infants had a slightly lower holding pressure than children and adults, although the holding pressure did not differ between children and adults. This finding probably represented the difficulty in getting the infants to go to sleep with the nasal mask and bias setup. Children had a tendency to become -limited at a lower PN than adults or infants. Children and infants attained a lower PN before arousal or obstruction occurred, compared with adults.


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  		Table 2. Nasal pressures during pressure-flow response testing

 
Figure 2 shows a typical pressure- tracing from a normal child during an intermittent challenge. Following a drop in PN, the first three breaths had low values, with a -limited pattern to the waveform. Breaths 4 and 5 were larger and showed a transition to a non--limited pattern, suggesting that activation of the upper airway muscles occurred at that point. To quantitate this change, the mean difference in inspiratory (as a percentage of baseline ) between breath 1 and breath 2 following the drop in PN was measured for each subject. Similarly, the differences between breath 1 and breath 3, and breath 1 and breath 5, were measured. In the children, there was no significant difference in between breath 1 vs. breath 2 (median –1%, range –32–27%) or between breath 1 vs. breath 3. However, there was a significant increase in between breaths 1 vs. 5 (median 15%, range –33–593%, P < 0.05). In infants, there was a highly significant increase in rates by breath 2 (median 5%, range –14–15%, P < 0.03 for breath 1 vs. breath 2; and P < 0.02 for breath 1 vs. 3). Adults had a nonsignificant decrease in between breaths 1 and 2 (median –20%, range –62–17%) and breaths 1 and 3, and a nonsignificant increase in by breath 5 (median 1%, range –83–197%).

Intraoral genioglossal EMG measurements were performed in five children during sleep. A typical example from an 11-yr-old boy is shown in Fig. 5. During gradual runs, there was a gradual increase in EMG activity as PN became increasingly negative (Fig. 5A). In contrast, during the intermittent runs (Fig. 5B), the EMG activity was at a low level for the first three breaths of negative pressure and began to increase only by the fourth breath. For the group as a whole, there was an increase in EMG activity, measured as a percentage of baseline activity, for breath 5 vs. breath 1 (P < 0.001).



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  		Fig. 5. , PN, raw genioglossal electromyography (EMGgg), moving average [moving time average (MTA)] of the EMGgg, and chest wall motion are shown from a child sleeping while wearing an intraoral EMG mouthpiece. A: portion of a gradual run. B: portion of an intermittent run. During the gradual run, the EMG increases incrementally, whereas, during the intermittent run, the EMG typically begins to increase only by the 4th breath.

 
With the use of the intermittent technique, Pcrit was similar between infants and normal children (Table 3). This was not due to a floor effect, as it remained true even when an extrapolated Pcrit without a cutoff point was used. The intermittent Pcrit was significantly more negative in the pediatric groups compared with the adults (P < 0.05 for both infants and children vs. adults). The slope was flatter in the infants than in the children (P < 0.001) and was flatter in both the infants and children than the adults (P < 0.0001 and P < 0.02, respectively).


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  		Table 3. Gradual vs. intermittent pressure-flow relationships

 
With the use of the gradual technique, both pediatric groups had a lower Pcrit and a flatter slope than the adults (Pcrit: P = 0.001 for infants vs. adults and P < 0.0001 for children vs. adults; slope: P < 0.0001 for both infants and children vs. adults); there was no significant difference between the infants and the children.

The group changes in slope for the gradual vs. the intermittent techniques are shown in Fig. 4. Eighty-five percent of children had a flatter slope with the use of the gradual technique compared with the intermittent technique (P < 0.01). In contrast, neither infants nor adults had a significant change between the two conditions (43 and 46%, respectively). There was no difference in Pcrit between the gradual and intermittent techniques in any of the groups. However, this may have been because many infants and children had a Pcrit cutoff of –25 cmH2O applied to them in both states.

The effect of the PFR technique on gas exchange was evaluated by measuring the changes in SaO2 and transcutaneous PCO2 from immediately before each gradual/intermittent run to just before arousal at the termination of each run. The median change in SaO2 was 0% for the intermittent technique and –1% for the gradual technique. The greatest individual change in SaO2 was –3%; no subject desaturated below 94%. The median change in transcutaneous PCO2 was 0 Torr for all challenges; the greatest increase in PCO2 for any individual was 2 Torr.

The correlation between age and PFR was evaluated. For the study group as a whole, there was a significant correlation between age and both the intermittent and the gradual slope (r = 0.66, P < 0.001; and r = 0.71, P < 0.001, respectively; Fig. 6). Because it is possible that older subjects had a greater slope of the pressure- curve (SPF) simply because they were larger and had a greater rate, we evaluated the difference in SPF corrected for height (the primary predictor for in pulmonary function testing) among the three age groups. There was no significant difference in SPF/height between children and infants (P = 0.40 for gradual SPF/height; P = 0.20 for intermittent SPF/height). Adults had a greater SPF/height than both the children and infants (P < 0.001 for adults vs. either infants or children for gradual SPF/height; P < 0.02 for intermittent SPF/height for adults vs. infants; P < 0.03 for intermittent SPF/height for adults vs. children).



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  		Fig. 6. Slope of the pressure- curve, with the use of the gradual technique, is plotted against age. There is a significant correlation between slope and age.

 
The correlation between age and PFR was also evaluated within the individual age groups. Pcrit was not evaluated as it was not a continuous variable, due to the imposed cutoff of –25 cmH2O. In the infants, there was a correlation between age and the intermittent slope (r = 0.49, P < 0.05) and a trend toward a positive correlation between age and the gradual slope (r = 0.46, not significant). Within the child and adult groups, there was no significant correlation between age and slope, and all of the correlation coefficients were very low.

CO2 Responses

CO2 responses were performed in children and adults by using the gradual technique. A few subjects who completed CO2 runs did not successfully complete intermittent room air runs, although all completed gradual room air runs. Therefore, the CO2 runs were compared with the gradual room air runs. In the children, median transcutaneous PCO2 was 46 Torr before the challenge and 48 Torr by the end of the challenge. In the adults, transcutaneous PCO2 was initially 45 Torr, increasing to 49 Torr by the end of the challenge.

In the normal children, hypercapnia resulted in increased for a given PN. A typical example is shown in Fig. 7. There appeared to be an interaction between the response to CO2 and the response to negative pressure as PN decreased. As a result of this interaction, there was a marked increase in Imax when the subject breathed CO2 compared with room air at mild levels of subatmospheric PN (e.g., –4 cmH2O in Fig. 7). As the subatmospheric pressure decreased (became more negative, e.g., –14 to –18 cmH2O in Fig. 7), there was a persistent but much smaller effect of CO2 on Imax. This suggests that, at high-pressure loads, the upper airway muscles were maximally activated in the normal children and could not increase their tone further, despite persistent stimulation by CO2. However, this interaction made it difficult to analyze the pressure- relationship. Therefore, data were evaluated by comparing Imax when subjects breathed room air vs. CO2 at atmospheric pressure (PN = 0 cmH2O). As only -limited breaths were evaluated, changes in the amount of were due to changes in upper airway properties, rather than changes in the overall ventilatory drive.



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  		Fig. 7. Typical example of pressure- relationships during room air ({bullet}) vs. hypercapnia (CO2; {circ}) in a child is shown. Hypercapnia resulted in increased inspiratory at each pressure level. However, this effect was more marked at low levels of subatmospheric pressure.

 
During CO2 testing, limitation began at a higher PN in the adults than in the children. Adults had a greater Imax when breathing room air than the children (Table 4). However, the change in Imax when breathing CO2 vs. room air, as a percentage of baseline (i.e., corrected for the differences in baseline values) was smaller in the adults than the children (P < 0.05). In the children, CO2 resulted in a significant increase in Imax, with 90% of subjects showing an increase during hypercapnia (P < 0.01). In contrast to the children, adults had a variable response, with only 50% showing an increase in (not significant).


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  		Table 4. Effect of CO2 on maximal inspiratory flow at atmospheric pressure (PN = 0) during sleep

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We have evaluated the dynamic upper airway responses to differing stimuli during sleep along the age spectrum. We found that 1) upper airway collapsibility was increased in adults compared with both infants and children, and 2) children had active upper airway dynamic responses to both negative pressure pulses and hypercapnia during sleep. In contrast, adults did not have upper airway activation in response to the applied stimuli. Infants appeared to have a very rapid response to negative pressure.

Upper Airway Pressure- Relationships

Our laboratory has previously used the Starling resistor model to objectively determine upper airway collapsibility (30, 32). This model, which has been well characterized for a number of biological systems, such as blood vessels (36) and the lower airways (39), has been shown to be applicable to the upper airway in both adults and children with obstructive sleep apnea syndrome (30, 32, 52). The model describes the major determinants of in terms of the mechanical properties of collapsible tubes. According to this model, under conditions of limitation, Imax is determined by the pressure changes upstream (nasal) to a collapsible locus of the upper airway and is independent of the downstream (tracheal) pressure generated by the diaphragm. In an isolated Starling resistor model, the sensitivity of the upstream pressure- relationship is represented by the SPF. The Pcrit occurs at the x-intercept of the pressure- curve (i.e., the pressure at which there is zero due to upper airway closure). Pcrit provides an objective and reproducible method for evaluating upper airway collapsibility (48). In adults, it can differentiate between normal, snoring, hypopneic, and apneic subjects (13). Pcrit correlates with the severity of apnea in children (32) and decreases after treatment of obstructive sleep apnea (32, 46).

Although Pcrit is a useful measurement in the disease state in children, our laboratory previously showed that Pcrit could not be determined in normal children, as their upper airway was very resistant to collapse (30). This resulted in an extremely negative Pcrit, such that the x-intercept of the pressure- curve could not be determined without extreme extrapolation. In addition, the pressure- curve had a much flatter slope. This demonstrated a major difference in upper airway regulation between children and adults, and the Starling resistor model may not be applicable to normal children under activated conditions. We, therefore, utilized a relatively hypotonic technique, which allowed us to partition the neuromotor and structural determinants of upper airway collapsibility (47). In an isolated Starling resistor model, Imax is determined solely by Pcrit and the resistance of the upper airway upstream to the site of collapse. However, in the intact human, the upper airway pressure- relationship reflects both upper airway structural factors and neuromotor control, as the upper airway is not merely a passive conduit affected by mechanical forces, but is also affected by activation of the upper airway muscles. The classic PFR performed in the past involved the application of increasingly more negative PN (32). This resulted in increasing activation of the upper airway muscles. In the present study, we compared this activated technique to a hypotonic technique. Positive PN suppresses upper airway tone (56), whereas reductions in PN result in increased upper airway tone (26). Previous studies in adults have shown that this effect of negative pressure takes at least three breaths before the upper airway is activated; our data support a similar response in children older than infancy (26, 47). Thus maintaining positive PN and then acutely dropping to negative pressure for a few breaths results in a relatively hypotonic airway. This hypotonic technique can be used to construct PFR curves for a functionally denervated upper airway, which can then be compared with PFR curves constructed for the activated airway.

Neuromotor Control of the Upper Airway

Neuromotor factors are important in maintaining upper airway stability. Studies using denervation of upper airway dilating muscles or postmortem measurements have shown that, when upper airway muscle function is decreased, the upper airway is more collapsible (9, 60). Conversely, stimulation of the upper airway muscles decreases collapsibility (49, 50). The factors modulating upper airway tone include sleep state, chemoreceptor afferents (57), upper airway pressure receptors (37), and tracheal traction (54). The upper airway response to subatmospheric pressure has been intensively studied. It is thought to be a centrally mediated reflex, as suggested by 1) functional magnetic resonance imaging studies showing activation of central nervous system centers in response to upper airway loading (15), 2) the fact that the upper airway response to disparate stimuli such as hypercapnia and inspiratory loading is similar (34), 3) the rapid timing of the response compared with voluntary activation (18), and 4) changes in the response to loading during sleep compared with wakefulness (7). The upper airway contains pressure receptors in the mucosa of the nasopharynx and larynx (44). These negative pressure receptors appear to be the same as those for CO2 (4), although they are separate from receptors for other stimuli, such as cold, , and irritants (44). Afferent stimuli are conducted along the trigeminal, glossopharyngeal, and vagal nerves (16). Central pathways have not been clearly delineated but are thought to involve the locus coeruleus, caudal raphe, mesopontine tegmentum, and medullary reticular formation (59). Stimulation of these subatmospheric pressure receptors results in both inspiratory and expiratory activation of numerous upper airway dilator muscles (16).

It is possible that factors other than activation of the upper airway muscles played a role in the change of the profile. This change was not due to arousal, as the EEG was monitored, and runs were terminated if arousal occurred. During CO2 and negative pressure administration, it is most likely that the change in inspiratory pattern was due to activation of the central nervous system, resulting in augmented upper airway muscle activity (19, 29, 57). This is considered most likely as subjects showed similar changes in SPF and Pcrit with the use of two very different techniques: pulses of subatmospheric pressure and CO2 inhalation. In addition, during CO2 challenges, it is possible that the inspired CO2 diminished fluctuations in chemical stimuli to the brain, thereby decreasing the gain of the respiratory controller and reducing central nervous system oscillations and their subsequent effect on the upper airway (27). Other factors that may have an effect on the waveform include changes in negative airway pressure (1) and changes in lung volumes due to changes in PN (1, 54); lower lung volumes are associated with increased Pcrit. The latter was unlikely to have been a major factor in the present study. Although lung volumes were not measured, it is likely that lung volumes would be lower during the long gradual runs, during which continuous subatmospheric pressure is applied, than during intermittent runs, during which the subject is placed on positive pressure between the five breath runs. Thus, if lung volume played a major role, it would be expected that subjects would have a more collapsible airway during the gradual than the intermittent runs, yet in the children the opposite result was noted.

Developmental Changes in Upper Airway Collapsibility

Infants and children have a narrower upper airway than adults. Nevertheless, they snore less and have fewer obstructive apneas (33). This could be due to either structural differences or differences in neuromotor regulation of the upper airway.

In the activated state, using the gradual technique, the children had a markedly more negative Pcrit and flatter slope than the adults. Upper airway neuromotor responses in adults have been reported in detail in the literature. During wakefulness, both CO2 and negative pressure result in increased upper airway activity (58). However, these responses are markedly diminished during sleep (38, 58). This was confirmed in the adults in our study. However, we found a significant difference between children and adults in this regard, with the normal children having preservation of upper airway responses to both negative pressure and hypercapnia during sleep. This may be due to a difference in central nervous system regulation of upper airway function. Normal children have a higher ventilatory drive than adults (14, 28, 53). It has been shown that there is a relationship between the occlusion pressure in 100 ms (a measure of ventilatory drive) and PFRs during sleep (30). Thus normal children may have increased upper airway dynamic responses during sleep due to the effect of an increased central ventilatory drive on the upper airway musculature. It should be noted that the stimuli used in this study were very subtle (i.e., a 3-mmHg increase in CO2 and a 3-breath pulse of negative pressure). It is possible that adults would have shown a response to a larger or more prolonged stimulus.

To determine whether the intermittent technique truly resulted in hypotonia, we compared the difference in between breath 1 following the drop in PN and the subsequent breaths. In the children, we typically noted a change to a non--limited pattern following breath 3 (Fig. 2). did not change between breaths 1 and breaths 2 and 3 but increased significantly by breath 5. This indicates that upper airway activation typically occurred after three breaths in the normal children. This was confirmed by EMG measurements in several children. Thus analyzing the first three breaths at each pressure drop did allow for the assessment of a relatively hypotonic airway.

The difference between children and adults using the intermittent technique was not as marked as that with the gradual technique. Nevertheless, even with the intermittent technique and a relatively hypotonic airway, the children had a lower Pcrit and a flatter slope than the adults. There are two possible explanations for this. One is that there are structural differences in the upper airway between children and adults. It is possible that the narrower upper airway in children is less compliant than in adults, or that adults have more laxity of the connective tissue and mucosa. Another explanation is that the intermittent technique did not result in total atonia of the airway in the children. Both theories are supported by data from Isono et al. (20). They studied upper airway collapsibility in anesthetized, paralyzed children, i.e., children with a totally flaccid upper airway. The mean closing pressure under those conditions was –8 ± 5 cmH2O, which was higher than that demonstrated in our subjects by using the intermittent technique (–25 cmH2O). Measurements from the two studies may not be directly comparable, as different techniques were used. However, in the study by Isono et al., as in ours, the children had a lower closing pressure than adults studied with the same technique, suggesting that structural differences do play some role.

Adults may have a greater SPF simply because they are larger and have a greater rate. However, this cannot explain all of our results. Although adults had a greater SPF/height than either infants or children, there was no significant difference in SPF/height between infants and children, despite the fact that the height difference between these two groups was far greater than between the children and adults (Table 1). Furthermore, differences in body size cannot account for the differences in Pcrit between the groups. In addition, differences in body size between groups cannot explain why children show a much greater response to negative pressure and hypercapnia than adults.

As with the older children, the infant upper airway was resistant to collapse, with a low Pcrit and a flat slope. However, in the infants, there was little difference in upper airway collapsibility between the gradual and the intermittent techniques. In addition, there was little variability between individual infant subjects. There are several possible reasons for the similarity of responses between the gradual and the intermittent techniques. In contrast to the older children, infants had rapid activation of the upper airway in response to negative pressure, occurring as early as the second breath after the drop in PN. This correlates very well with the work of Gauda et al. (12), who showed that an EMG response to upper airway occlusion occurred by the second breath in 74% of trials in premature neonates, and by the third breath in 80%; Carlo et al. (10) found similar results. Thus it is most likely that the infants had active upper airway responses during sleep but that the mechanism and timing of these responses differed from those of the older age groups. Other studies suggest the presence of active upper airway neuromotor responses in infants. Roberts et al. (41) examined the closing pressure in normal young infants and found it to be –4 ± 3 cmH2O. The same group found that the upper airway closing pressure in infant cadavers was –1 ± 2 cmH2O (60). Different techniques were used for the two studies, which makes it difficult to directly compare the results of these studies to each other or to our data. Nevertheless, these data suggest that, in the postmortem or paralyzed state, where there is no neuromotor activation, the infant upper airway is more collapsible than in the intact state. Thus the literature supports the contention that the infant upper airway remains patent during sleep due to continued activation of upper airway muscles. In the present study, we did not test hypercapnic responses in the infants, as infant testing was difficult due to frequent arousals in response to subatmospheric pressure. However, further studies that use other techniques to evaluate infant upper airway responses would be desirable to confirm our speculations. An alternative explanation would be that the infants' flat slope and low Pcrit were due to structural changes, i.e., that the infant upper airway was smaller and stiffer than that of older subjects. This would be surprising. In general, infants have decreased muscle tone compared with older subjects. We are not aware of any direct comparisons of upper airway muscle tone between infants and other age groups. However, the muscles of the head and neck, such as those supporting head control, are clearly weaker in infants. Similarly, the cartilaginous structures of the upper airway in infants tend to be floppy, frequently giving rise to tracheomalacia and laryngomalacia. Furthermore, a study of anesthetized, paralyzed infants showed that the upper airway in this totally atonic state was more collapsible than that of older children (20, 21). Finally, structural changes would not explain the differences in breaths 1 and 2 following negative pressure in the infants.

We evaluated the relationship between PFR parameters and age. We confirmed our previous finding showing that the gradual slope correlated with age (30). We also found a similar relationship between the intermittent slope and age. Isono et al. (21) previously showed an inverse correlation between upper airway collapsibility and age in the anesthetized, paralyzed state in infants. We found contradictory results in the infants. In the present study, there was a positive correlation between age and the intermittent slope in the infants, as well as a trend toward a correlation between age and the gradual slope. The difference between the two studies is most likely due to the differences in techniques. Isono et al. studied a totally passive airway, i.e., an anesthetized and paralyzed preparation. As a result, their closing pressures reflect anatomic changes. In contrast, we studied infants during natural sleep, when some neuromotor tone was present. This suggests that younger infants have increased upper airway neuromotor activity during sleep than older infants.

Methodological Limitations

In this study, upper airway dynamics were assessed by evaluating changes in during -limited breaths. Upper airway EMG measurements were obtained in only a few subjects. It is difficult to obtain EMG measurements in children undergoing research protocols, as invasive techniques cannot be used. Although intraoral EMG measurements have been made in neonates, it was not practical to add intraoral mouthpieces to the onerous equipment (nasal mask, negative pressure, CO2 and monitoring electrodes) used in this research protocol and expect these young children to have sustained, natural sleep. Furthermore, EMG signals are hard to quantitate and compare between individuals, especially in children too young to cooperate with specific calibration maneuvers (34). In addition, changes in EMG signals do not necessarily correspond to changes in muscle function (i.e., changes in muscle length). Therefore, to verify that the intermittent technique did, in fact, represent a relatively hypotonic airway, we analyzed the breath effect of changes in following acute drops in PN. This confirmed differences in neuromotor activation between the age groups. Nevertheless, future studies including more comprehensive EMG measures would be desirable.

Analysis of the gradual Pcrit was difficult in the infants and children, due to some of the very flat slopes generated. We, therefore, evaluated the gradual PFR in two ways: 1) by determining the slope of the response and 2) by arbitrarily assigning a Pcrit cutoff of –25 cmH2O. This cutoff point was chosen as it was just below the most negative pressure deliverable by our equipment. The alternative was to extrapolate data far beyond what was actually measured. This did not seem reasonable, as some of the slopes were extremely flat, so that extrapolated Pcrit values were as low as –165 cmH2O. However, assigning a cutoff point resulted in minimizing differences between the pediatric groups and the adults. Nevertheless, although the cutoff point resulted in smaller absolute differences between the groups, the relationship between groups was not altered compared with the use of the extrapolated data (see Fig. 4). Use of the cutoff level may have resulted in a floor effect that prevented us from determining significant differences between the infants and the children.

It is possible that the gradual technique resulted in upper airway activation by causing hypoxemia or hypercapnia, rather than as a direct effect of subatmospheric pressure. However, in view of the minimal changes in SaO2 and PCO2 during the challenges, it is unlikely that chemoreflexes played a major role. Even if this were the case, it would still be an indication of upper airway neuromotor activation.

Conclusion

We have shown that normal infants and children have a less collapsible upper airway than adults, consistent with the clinical finding that snoring is less common in the pediatric age groups. Our data suggest that this decrease in collapsibility is due primarily to the preservation of upper airway neuromotor responses in normal children during sleep. The timing and degree of upper airway neuromotor activation differ over the course of development. Further study is required to elucidate the mechanisms involved in maintaining airway patency in infants.


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C. L. Marcus was supported by General Clinical Research Center Grant RR-00052, The Johns Hopkins Hospital, Baltimore, MD, and by National Heart, Lung, and Blood Institute Grant HL-58585. L. B. Fernandes Do Prado was supported by Fundação de Amparo a Pesquisa do Estado de São Paolo (The State of São Paulo Foundation) Grant 1999/08189-61.


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The authors thank Peter Hill for supplying modified CPAP equipment to provide subatmospheric pressure. We are grateful to all of the volunteers and their families for their enthusiastic participation in this study.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. L. Marcus, Div. of Pediatric Pulmonology, Wood Bldg., 5th floor, Children's Hospital of Philadelphia, 34th St. & Civic Center Blvd., Philadelphia, PA 19104 (E-mail: marcus{at}email.chop.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.


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  1. Aittokallio T, Saaresranta T, Polo-Kantola P, Nevalainen O, and Polo O. Analysis of inspiratory flow shapes in patients with partial upper-airway obstruction during sleep. Chest 119: 37–44, 2001.
  2. American Thoracic Society. Standards and indications for cardiopulmonary sleep studies in children. Am J Respir Crit Care Med 153: 866–878, 1996.
  3. Anders T, Emde R, and Parmelee A (Editors). A Manual of Standardized Terminology, Techniques, and Criteria for Scoring of States of Sleep and Wakefulness in Newborn Infants. Los Angeles, CA: UCLA Brain Information Service, NINDS Neurological Information Network, 1971.
  4. Anderson JW, Sant'Ambrogio FB, Orani GP, Sant'Ambrogio G, and Mathew OP. Carbon dioxide-responsive laryngeal receptors in the dog. Respir Physiol 82: 217–226, 1990.
  5. [Anon]. EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 15: 173–184, 1992.
  6. [Anon]. Sleep-related breathing disorders in adults: recommendations for syndrome definition, and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 22: 667–689, 1999.
  7. Aronson RM, Onal E, Carley DW, and Lopata M. Upper airway and respiratory muscle responses to continuous negative airway pressure. J Appl Physiol 66: 1373–1382, 1989.
  8. Boudewyns A, Punjabi N, Van de Heyning PH, De Backer WA, O'Donnell CP, Schneider H, Smith PL, and Schwartz AR. Abbreviated method for assessing upper airway function in obstructive sleep apnea. Chest 118: 1031–1041, 2000.
  9. Brouillette RT and Thach BT. A neuromuscular mechanism maintaining extrathoracic airway patency. J Appl Physiol 46: 772–779, 1979.
  10. Carlo WA, Miller MJ, and Martin RJ. Differential response of respiratory muscles to airway occlusion in infants. J Appl Physiol 59: 847–852, 1985.
  11. Condos R, Norman RG, Krishnasamy I, Peduzzi N, Goldring RM, and Rapoport DM. Flow limitation as a noninvasive assessment of residual upper-airway resistance during continuous positive airway pressure therapy of obstructive sleep apnea. Am J Respir Crit Care Med 150: 475–480, 1994.
  12. Gauda EB, Miller MJ, Carlo WA, Difiore JM, Johnsen DC, and Martin RJ. Genioglossus response to airway occlusion in apneic versus nonapneic infants. Pediatr Res 22: 683–687, 1987.
  13. Gleadhill IC, Schwartz AR, Schubert N, Wise RA, Permutt S, and Smith PL. Upper airway collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev Respir Dis 143: 1300–1303, 1991.
  14. Gozal D, Arens R, Omlin KJ, Marcus CL, and Keens TG. Maturational differences in step vs. ramp hypoxic and hypercapnic ventilatory responses. J Appl Physiol 76: 1968–1975, 1994.
  15. Gozal D, Omidvar O, Kirlew KAT, Hathout GM, Hamilton R, Lufkin RB, and Harper RM. Identification of human brain regions underlying responses to resistive inspiratory loading with functional magnetic resonance imaging. Proc Natl Acad Sci USA 92: 6607–6611, 1995.
  16. Horner RL. Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 19: 827–853, 1996.
  17. Horner RL, Innes JA, Murphy K, and Guz A. Evidence for reflex upper airway dilator muscle activation by sudden negative airway pressure in man. J Physiol 436: 15–29, 1991.
  18. Hudgel DW, Hendricks C, and Dadley A. Alteration in obstructive apnea pattern induced by changes in oxygen- and carbon-dioxide-inspired concentrations. Am Rev Respir Dis 138: 16–19, 1988.
  19. Isono S, Shimada A, Utsugi M, Konno A, and Nishino T. Comparison of static mechanical properties of the passive pharynx between normal children and children with sleep-disordered breathing. Am J Respir Crit Care Med 157: 1204–1212, 1998.
  20. Isono S, Tanaka A, Ishikawa T, and Nishino T. Developmental changes in collapsibility of the passive pharynx during infancy. Am J Respir Crit Care Med 162: 832–836, 2000.
  21. Kahn A, Franco P, Kato I, Groswasser J, Dan B, Scaillet S, and Kelmanson IA. Breathing during sleep in infancy. In: Sleep and Breathing in Children—A Developmental Approach, edited by Loughlin GM, Marcus CL, and Carroll JL. New York: Dekker, 2000, p. 405–422.
  22. Katz ES and White DP. Genioglossus activity in children with obstructive sleep apnea during wakefulness and sleep onset. Am J Respir Crit Care Med 168: 664–670, 2003.
  23. Kleinman RE. Obesity. In: Pediatrics, edited by Rudolph AM. Norwalk, CT: Appleton & Lange, 1987, p. 205–208.
  24. Launois SH, Feroah TR, Campbell WN, Issa FG, Morrison D, Whitelaw WA, Isono S, and Remmers JE. Site of pharyngeal narrowing predicts outcome of surgery for obstructive sleep apnea. Am Rev Respir Dis 147: 182–189, 1993.
  25. Longobardo GS, Gothe B, Goldman MD, and Cherniack NS. Sleep apnea considered as a control system abnormality. Respir Physiol 50: 311–333, 1982.
  26. Marcus CL, Glomb WB, Basinski DJ, Davidson SL, and Keens TG. Developmental pattern of hypercapnic and hypoxic ventilatory responses from childhood to adulthood. J Appl Physiol 76: 314–320, 1994.
  27. Marcus CL, Lutz J, Carroll JL, and Bamford O. Arousal and ventilatory responses during sleep in children with obstructive sleep apnea. J Appl Physiol 84: 1926–1936, 1998.
  28. Marcus CL, Lutz J, Hamer A, Smith PL, and Schwartz A. Developmental changes in response to subatmospheric pressure loading of the upper airway. J Appl Physiol 87: 626–633, 1999.
  29. Marcus CL, McColley SA, Carroll JL, Loughlin GM, Smith PL, and Schwartz AR. Upper airway collapsibility in children with obstructive sleep apnea syndrome. J Appl Physiol 77: 918–924, 1994.
  30. Marcus CL, Omlin KJ, Basinki DJ, Bailey SL, Rachal AB, Von Pechmann WS, Keens TG, and Ward SL. Normal polysomnographic values for children and adolescents. Am Rev Respir Dis 146: 1235–1239, 1992.
  31. Mezzanotte WS, Tangel DJ, and White DP. Waking genioglossal electromyogram in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 89: 1571–1579, 1992.
  32. NHLBI. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Am J Clin Nutr 68: 899–917, 1998.
  33. Permutt S and Riley RL. Hemodynamics of collapsible vessels with tone: the vascular waterfall. J Appl Physiol 18: 924–932, 1963.
  34. Philip-Joet F, Marc I, and Series F. Effects of genioglossal response to negative airway pressure on upper airway collapsibility during sleep. J Appl Physiol 80: 1466–1474, 1996.
  35. Pillar G, Malhotra A, Fogel RB, Beauregard J, Slamowitz DI, Shea SA, and White DP. Upper airway muscle responsiveness to rising PCO2 during NREM sleep. J Appl Physiol 89: 1275–1282, 2000.
  36. Pride NB, Permutt S, Riley RL, and Bromberger-Barnea B. Determinants of maximal expiratory flow from the lungs. J Appl Physiol 23: 646–662, 1967.
  37. Rechtschaffen A and Kales A. A Manual of Standardized Terminology: Techniques and Scoring Systems for Sleep Stages of Human Subjects. Los Angeles, CA: UCLA Brain Information Service/Brain Research Institute, 1968.
  38. Roberts JL, Reed WR, Mathew OP, Menon AA, and Thach BT. Assessment of pharyngeal airway stability in normal and micrognathic infants. J Appl Physiol 58: 290–299, 1985.
  39. Rosenfeld RM and Green RP. Tonsillectomy and adenoidectomy: changing trends. Ann Otol Rhinol Laryngol 99: 187–191, 1990.
  40. Rosner B, Prineas R, Loggie J, and Daniels SR. Percentiles for body mass index in U.S. children 5 to 17 years of age. J Pediatr 132: 211–222, 1998.
  41. Sant'Ambrogio G, Tsubone H, and Sant'Ambrogio FB. Sensory information from the upper airway: role in the control of breathing. Respir Physiol 102: 1–16, 1995.
  42. Schwartz AR, Gold AR, Schubert N, Stryzak A, Wise RA, Permutt S, and Smith PL. Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 144: 494–498, 1991.
  43. Schwartz AR, O'Donnell CP, Baron J, Schubert N, Alam D, Samadi SD, and Smith PL. The hypotonic upper airway in obstructive sleep apnea. Am J Respir Crit Care Med 157: 1051–1057, 1998.
  44. Schwartz AR, Schubert N, Rothman W, Godley F, Marsh B, Eisele D, Nadeau J, Permutt L, Gleadhill I, and Smith PL. Effect of uvulopalatopharyngoplasty on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 145: 527–532, 1992.
  45. Schwartz AR, Thut DC, Brower RG, Gauda EB, Roach D, Permutt S, and Smith PL. Modulation of maximal inspiratory airflow by neuromuscular activity: effect of CO2. J Appl Physiol 74: 1597–1605, 1993.
  46. Schwartz AR, Thut DC, Russ B, Seelagy M, Yuan X, Brower RG, Permutt S, Wise RA, and Smith PL. Effect of electrical stimulation of the hypoglossal nerve on airflow mechanics in the isolated upper airway. Am Rev Respir Dis 147: 1144–1150, 1993.
  47. Smith PL, Wise RA, Gold AR, Schwartz AR, and Permutt S. Upper airway pressure-flow relationships in obstructive sleep apnea. J Appl Physiol 64: 789–795, 1988.
  48. Springer C and Wasserman K. Evidence that maturation of the peripheral chemoreceptors is not complete in childhood. Respir Physiol 74: 55–64, 1988.
  49. Stanchina ML, Malhotra A, Fogel RB, Trinder J, Edwards JK, Schory K, and White DP. The influence of lung volume on pharyngeal mechanics, collapsibility, and genioglossus muscle activation during sleep. Sleep 26: 851–856, 2003.
  50. Strohl KP and Redline S. Nasal CPAP therapy, upper airway muscle activation, and obstructive sleep apnea. Am Rev Respir Dis 134: 555–558, 1986.
  51. Weiner D, Mitra J, Salamone J, and Cherniack NS. Effects of chemical stimuli on nerves supplying upper airway muscles. J Appl Physiol 52: 530–536, 1982.
  52. Wheatley JR, Tangel DJ, Mezzanotte WS, and White DP. Influence of sleep on response to negative airway pressure of tensor palatini muscle and retropalatal airway. J Appl Physiol 75: 2117–2124, 1993.
  53. Widdicombe J. Upper airway reflexes. Curr Opin Pulm Med 4: 376–382, 1998.
  54. Wilson SL, Thach BT, Brouillette RT, and Abu-Osba YK. Upper airway patency in the human infant: influence of airway pressure and posture. J Appl Physiol 48: 500–504, 1980.



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