Upper airway muscle activity and the thoracic volume dependence of upper airway resistance ROBERT M. ARONSON, DAVID W. CARLEY, ERGON ONAL, JEROME WILBORN, AND MELVIN LOPATA Section of Pulmonary Medicine, Department of Internal Medicine, Chicago College of Osteupathic Medicine, Chicago 60615; Section of Respiratory and Critical Care Medicine, Department uf Medicine, University of Illinois College of Medicine, Chicago 60680; and University of Illinois Hospital and Veterans Administration West Side Medical Center, Chicago, Illinois 60612 ARONSON,ROBERT M., DAVID W. CARLEY, ERGON ~NAL,JEROME WILBORN, AND MELVIN LOPATA. Upper airway mu&e activity
and the thuracic
volume
dependence
of upper
airway
re-
sistance. J. Appl. Physiol. 70(l): 430-438, 1991.-Although a thoracic volume dependence of upper airway resistance and caliber is known to exist in seated subjects, the mechanisms mediating this phenomenon are unknown. To test the hypothesis that actively altered end-expiratory lung volume (EELV) affects upper airway resistance in the supine position and to explore the mechanisms of any EELV-induced resistance changes, we studied five normal males during wakefulness. Supraglottic upper airway resistance (Ruaw) was calculated at an inspiratory flow of 0.1 l/s. The genioglossal electromyogram was obtained with indwelling wire electrodes and processed as moving time average. End-tidal CO, was monitored by infrared analyzer. Observations were made during four 20breath voluntary maneuvers: two at high and two at low EELV in each subject. Each maneuver was preceded by a control period at functional residual capacity. At high lung volume the EELV was increased by 2.23 t 0.54 (SD) liters; Ruaw decreased to 67.8 zt 35.1% of control, while tonic and phasic genioglossal activities declined to 79.0 r4 23.1 and 72.4 t 29.8%) respectively. At low lung volume the EELV was decreased by 0.86 t 0.23 l’t1 ers. Ruaw increased to 178.2 -t 186.8%, while tonic and phasic genioglossal activities increased to 243.0 t 139.3 and 249.1 t 146.3%, respectively (P < 0.0001 for all). The findings were not explained by COz perturbations or respiratory pattern. Multiple linear regression analysis indicated that the genioglossal responses blunted the EELV-induced changes in upper airway patency. We conclude that actively mediated increases in EELV in the supine position are associated with reduced Ruaw, decreases in EELV are associated with increased Ruaw, and genioglossal activity is not the means by which these relationships occur. The generation of tension in muscles linking the thorax to the upper airway and/ or the transmission of force via the trachea may explain the
observations. These findings suggest that fluctuations in EELV attendant
to respiratory
instability
during
sleep may
predispose to upper airway occlusion. genioglossal electromyogram; occlusive apnea; upper airway occlusion; sleep apnea; end-expiratory lung volume; functional residual capacity
PREVIOUS WORK from our laboratory
breath-to-breath 430
fluctuations
demonstrated that in end-expiratory lung
0161-7567/91
$1.50 Copyright
volume (EELV) occur during the cyclic breathing characteristic of obstructive sleep apnea (2). However, little is understood about the relationship of changes in lung volume to upper airway patency. An association between upper airway caliber and actively mediated changes in thoracic volume has been described in seated obese and nonobese normal subjects (8, 10, 16) and in seated obese and nonobese patients with obstructive sleep apnea (8, 16). Similarly, an inverse relationship between upper airway resistance (Ruaw) and actively mediated changes in EELV has been described in seated normal subjects (28). Whether similar relationships would persist during actively induced lung volume changes in supine humans is not known. The means by which the thoracic volume dependence of upper airway patency occurs is unknown. It has been speculated that this phenomenon may occur through the activity of upper airway dilating muscles (8-10, 16), which theoretically would be stimulated concurrently with the inspiratory muscles by linked brain stem motoneurons (16) or influenced by inflation reflexes (8-10, 16). However, the validity of this explanation has never been specifically examined. Next, pharyngeal mucosal blood volume, which has been shown to affect upper airway caliber (18), may be affected by hemodynamic shifts resulting from lung volume changes. Finally, the thoracic volume dependence of upper airway patency may occur through mechanical linkages between the thorax and upper airway. Recent work by Van de Graaff (30) has strongly supported the hypothesis that such mechanical linkages mediate declines in Ruaw during activation of thoracic inspiratory muscles in supine tracheotomized dogs. This work demonstrated that declines in Ruaw occurred during spontaneous inspiration, during inspiration induced by phrenic nerve stimulation in apneic animals, and during spontaneous inspiration in animals with upper airway denervation; elimination of inspiratory declines in Ruaw required the transection of all ventrolateral cervical structures. In obstructive sleep apnea, the breath-by-breath fluctuations in EELV occur during spontaneous breathing (with thoracic inspiratory muscle activation) and generally in the recumbent position. Thus we proceeded to
0 1991 the American
Physiological
Society
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UPPER
DC ML RH VC TC
32 47 32 30 28
Mean st SD
34-+8
AIRWAY
180.3 167.6 180.3 185.4 182.9 179.3t6.9
MUSCLE
73.2 58.2 74.1 84.1 69.1 71.7k9.4
ACTIVITY,
111.2 116.7 85.7 87.5 107.5 101.7t14.2
RESISTANCE, AND LUNG VOLUME
120.2 110.4 98.4 93.1 106.4 105.7t10.5
FE&, forced expiratory volume in 1 s; FVC, forced vital capacity; FRC, functional Ruaw, upper airway resistance during pooled control periods (means t SD).
assess whether actively mediated alterations in EELV affect Ruaw in supine humans and explored the mechanisms of any such phenomenon by the concomitant measurement of upper airway muscle activity.
76.1 80.9 72.2 79.6 85.2
residual
78.8t4.9
capacity measured
431
116.1 92.2 104.5 81.2 118.8 102.6t15.9
3.5k2.2 7.7t3.3 3.5tl.5 2.5tl.6 1.6tl.O 3.8k2.9
by body plethysmography;
Five normal nonsnoring male volunteers were studied after they signed an informed consent form approved by the Institutional Review Board of the University of Illinois at Chicago. The subjects were of normal body weight and were free of pulmonary disease (Table 1). A tight-fitting nasal mask (Respironics, Monroeville, PA) was worn by all subjects. Tidal volume (VT) and inspiratory flow were measured by a pneumotachograph (Fleisch no, 3, Hewlett-Packard 47303A) in four subjects and by a IO-liter water seal spirometer (Warren E. Collins, Braintree, MA) in one subject. Inspiratory and expiratory durations (TI and TE, respectively) were measured from the flow tracing. Minute ventilation (VI) was calculated from VT, TI, and TE. Inspiratory pressure across the supraglottic upper airway was assessed by a balloon-tip catheter positioned by use of endoscopic guidance at the tip of the epiglottis and referenced to mask pressure by a Gould-Statham differential transducer (PMlSlTC). Multiple holes were created in the distal catheter to ensure accurate transmission of pressure to the catheter lumen. Splints were placed in the nostrils to prevent changes in anterior nasal resistance. The catheter emerged from the nose through a splint and was secured with tape to prevent migration. Inspiratory Ruaw was calculated at a flow of 0.1 l/s (4). End-tidal CO, was monitored by infrared analyzer (Beckman LB-Z) with a sampling cannula placed in one of the nasal splints. Genioglossal electromyography was performed with bilateral indwelling wire electrodes (platinum-1076 iridium alloy) placed perorally. The signal was amplified, band-passed (30-600 Hz), rectified, moving time averaged (Paynter filter, 0.1 s time constant), and quantified as both phasic inspiratory change from expiratory baseline (EMGge) and “tonic” expiratory activity measured from electrical zero (EMGgeEEL). Direct current-coupled respiratory inductive plethysmography (Respitrace, Ardsley, NY) was used to measure the changes in EELV (2,3). The coils were taped to the thorax and abdomen in a nonbinding manner to pre-
squares (11), and validation to prove accuracy to within tlO% of simultaneous spirometry over a wide range of relative rib cage and abdominal contributions to VT was performed in all subjects. The stability of coil position was confirmed at the conclusion of each study. All subjects were studied in the supine position. The inductive plethysmograph sum signal was displayed on an oscilloscope that the subjects viewed by mirror, facilitating the maintenance of a given EELV. The pneumotachograph VT tracing was not used for this purpose because the device incorporated separate potentiometers for inspiratory and expiratory calibration; small differences in these calibrations appear as shifts in EELV over time. Observations were made during four maneuvers (two 20-breath periods at both high and low EELVs) in each subject. The EELVs obtained were determined empirically as the highest and lowest end-expiratory volumes that the subjects could comfortably maintain without visible thoracic spine or neck flexion. On the basis of data associating changes in respiratory pattern with alterations in Ruaw (28), during the maneuvers to high and low EELV, we required that the subjects attempt to superimpose the sum signal over a drawing of the resting pattern, which was traced to the oscilloscope screen during the ZOobreath control period that preceded each maneuver. Overall reasonable consistency was noted in raw EMGgeEEL and EMGge mean values between the four control periods (respective coefficients of variation 9.3, 11.6,11.5,71.6, and 24.7 and 16.9,22.2,6.1,15.9, and 28.5% in subjects VC, RH, TC, ML, and DC; the value of 71.6% occurred in the only subject undergoing electrode replacement in midstudy). However, one-way analysis of variance (ANOVA) performed for each subject revealed the differences between control periods to be statistically significant (P c 0.01) for both parameters (except EMGge in subject TC, P > 0.30). We thus chose to normalize to pool data. The breath-by-breath values for EMGge, EMGgeEEL, Ruaw, VT, VI, TI, and TEwere divided by their respective mean values during the control period that preceded each maneuver. Breath-by-breath values for the changes in rib cage, abdominal, and summated end-expiratory levels from their respective mean control period positions were recorded (ARC EEL, AAB EEL, and ASUM EEL, respectively). In addition, the change in exhaled CO, fraction (FET,,,) from the control period mean was calculated on a breath-by-breath
vent
basis during
METHODS
slippage.
Calibration
was by the method
of least
each maneuver.
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432
UPPER
AIRWAY
TABLE 2. Changes in FETED,, Tr, TE, low end-expiratory lung volumes Subj
MUSCLE VT,
ACTIVITY,
RESISTANCE,
AND
LUNG
VOLUME
I%, RC EEL, AB EEL, and SUM EEL at high and
A F’ET~~ Composition, %
A TI,
ATE,
AVT,
Air I,
ARC EEL,
%
%
%
%
liters
A AB EEL, liters
A SUM EEL, liters
0.03t0.43 0.26t0.37
1.7k20.3 -24.Ok24.8
-6.4-1-26.2 4.8k23.3
-14.9t27.2 -23.4k25.3
2.22kO.22 -0.43t0.14
-0.05t0.38 -0.17+0.15
2.17t0.45 -0.60t0.12
-0.OhO.25 0.33t0.33
16.5k23.3 17.1k24.8
-10.8t24.5 -26.7t20.6
-24.9t16.2
-2.7t23.1 -18.3-1-17.4
1.55t0.10 -0.65t0.13
0.51t0.10 -0.30t0.05
2.06t0.12 -0.94t0.13
O.llt0.28 -0.29~~0.17
28.Ok29.9 11.7k29.5
2.4t31.1 -10.6k22.3
28.2t21.7 18.0t13.8
15.6t23.5 19.9t20.3
l.llt0.32 -0.41t0.26
0.43t0.17 -0.62t0.10
1.54t0.26 -1.02t0.22
-1.00+0*19 -0.66t0.20
18.3_+30.0 -1.ot19.1
-3.6t20.0 18.8t31.9
31.0t23.9 22.5t28.3
25.7229.2 13.4-t-46.9
1.93kO.47 -1.04t0.18
0.62t0.15 0.27t0.09
2.54t0.45 -0.77t0.14
0.06t0.25 -0.17t0.14
1.0+14.3 1.4kl6.7
16.8t20.6 6.8t14.0
-3.8t11.2 13.0t12.2
1.43-+0.x3 -0.44t0.14
1.35t0.13 -0.55t0.23
2.77t0.28 -0.99xk0.19
-0.lW0.52 -0.14t,o.44
12.8k26.2 O.Ok27.1
-0.5t26.2 O.lt27.4
1.67~~0.48 -0.59t0.30
0.56kO.50 -0.27t0.36
2.2320.54 -0.86t0.23
RH
H L
-19.2t18.5 -29.5t25.1
TC
H L
-2.Ot15.9
ML
H L VC H
L DC H L Pooled H L
Values are means + SD of changes from preceding control
6.6-t-27.2 1.21k30.0
-10.9-tl4.5 8.9tl6.6 2.7k28.7 1.3t32.9
period. H, high end-expiratory
The statistical significance and reproducibility of changes in EMGge, EMGgeEEL, and Ruaw during the maneuvers to high and low EELV were assessed by twoway repeated measures ANOVA. The stability of Ruaw, EELV, EMGge, EMGgeEEL, and FETED, during the course of the 20-breath maneuvers at high and low lung volume was evaluated by one-way ANOVA. Finally, because the results did not demonstrate an inverse relationship between genioglossal activity and Ruaw (see RESULTS), we utilized a multiple regression analysis to investigate whether the alterations in EMGge and EMGgeEEL may have served to blunt the EELV-associated changes in upper airway patency. Although the protocol did not include graded EELV changes in individual subjects, the pooled observations contained a wide range of volumes above and below supine functional residual capacity (FRC) (Table 2). The relationship between Ruaw and lung volume in individual subjects has been shown to be inverse and curvilinear, creating a linear relationship between upper airway conductance (Guaw) and lung volume (7). Thus Guaw (l/raw Ruaw, 1 s-l l cmH,O-I) was used as the dependent variable in the multiple linear regression analysis. l
RESULTS
Ruaw during all control periods was 3.8 t 2.9 (SD) cmH,O .l-1 4s-l (Table 1). During maneuvers to high volume, EELV was increased by 2.23 t 0.54 liters (range 1.54 t 0.26 to 2.77 t 0.28; Table 2). Phasic and end-expiratory genioglossal activity declined (Figs. l-3) to 72.4 + 28.9 and 79.0 t 23.1% of control, respectively. Despite the declines in genioglossal activity, Ruaw at high EELV fell to 67.8 t 35.1% of control (Fig. 4). During maneuvers to low volume, EELV was decreased by 0.86 t 0.23 liter (range 0.60 t 0.12 to 1.02 t 0.22; Table 2). Phasic and end-expiratory genioglossal activity increased (Figs. l-3) to 249.1 t 146.3 and 243.0 t 139.3% of
lung volume; L, low end-expiratory
lung volume.
control, respectively. Despite the increases in genioglossal activity, Ruaw at low EELV increased to 178.2 t 186.8% of control (Fig. 4). The changes in Ruaw, EMGge, and EMGgeEEL were highly significant during maneuvers to both high and low EELV (P c 0.0001 for all). No statistically significant effect of first vs. second trial was noted for Ruaw or EMGge during maneuvers to high EELV or for EMGgeEEL during maneuvers to low EELV. The significant trial effects noted for EMGgeEEL (P < 0.004, high EELV) and Ruaw and EMGge (P < 0.0005 and 0.0001, low EELV) were due to quantitative rather than qualitative differences, Similarly, although obvious intersubject variability was present, it was overwhelmingly quantitative rather than qualitative in nature (Figs. 2-4). In contrast to the qualitative consistency of the genioglossal and resistance responses, the changes in endtidal CO, and respiratory pattern during high and low EELV periods were inconsistent (Table 2). Although significant increases in TI were noted in three of the five subjects during maneuvers to high EELV, no consistent overall trends to increases or decreases in TI, TE, VT, VI, or end-tidal CO, were otherwise noted during maneuvers to either high or low EELV (Table 2). Thus, although individual subjects demonstrated deviation from their resting respiratory patterns despite the aid of visual feedback, there was no overall consistency to the pattern of this deviation. No significant changes in Ruaw, EELV phasic or endexpiratory genioglossal activity, or FET,,, were noted for the group over the course of the 209breath maneuvers at either high or low lung volume (P > 0.56 for all). The inclusion of ASUM EEL, EMGge, and EMGgeEEL as independent variables in a multiple linear regression revealed that ASUM EEL and EMGge each made significant independent contributions to the changes in Guaw (P < 0.0001 and 0.0004, respectively) such that Guaw increased with increases in lung volume
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UPPER AIRWAY MUSCLE ACTIVITY, RESISTANCE, AND LUNG VOLUME
433
LMGge
EMGge
I I1.5
uT hh
-
60
SEC.
-
FIG. 1. Tracings of genioglossal electromyogram (EMGge), spirogram (VT), and expired CO2 (FET~~J during maneuvers to high (t@ and low (bottom) end-expiratory lung volumes. Obvious declines of phasic and end-expiratory genioglossal activity occur at high EELV, and increases occur at low EELV. These changes in EMGge are not explained by changes in FETED,.
and phasic genioglossal activity. The substitution of ARC EEL and AAB EEL for ASUM EEL in the analysis revealed that the contribution of lung volume to Guaw was explained by the changes in ARC EEL (P < O.OOOl), whereas AAB EEL added no significant independent contribution to the model. Because we measured changes from supine FRC rather than absolute supine lung volumes, and because intersubject differences in upper airway caliber have been related to differences in body surface area and lung volume (lo), the multiple regression analysis was repeated with Guaw normalized to its control period mean, with Guaw divided by absolute seated FRC, and with the lung volume changes nor-
malized to seated FRC. In each instance, phasic genioglossal activity and the changes in lung volume each made significant independent positive contributions to Guaw, with the lung volume contribution always being through the rib cage compartment. DISCUSSION
This study demonstrates that significant decreases in supraglottic resistance and genioglossus muscle activity occur with actively mediated increases in EELV in supine normal subjects. Similarly, significant increases in resistance and genioglossus activity occur with active
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434
UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND
LUNG
VOLUME
+ P
LOUJ IEEtlJ --HIGH
EELU
3.67 4 3.4. 4 3.2.
EMGge
, 39 I 2%
Normalized
2.6* 2.49 I 2.2. , 2. 1.8= 4 1 .6. 4 1.4m
.6 .4
SUBJECT
RH
TC
2. Values for phasie genioglossal activity at high and low EELV consistent increases at low and decreases at high EELV. FIG.
reductions in EELV. Thus an inverse relationship between Ruaw and actively generated changes in EELV has been confirmed in supine humans. Furthermore, it has been shown that this phenomenon is not mediated by genioglossus muscle activity. Multiple linear regression analysis indicates that the genioglossus muscle responses act to blunt the EELV-induced changes in upper airway patency. Finally, the thoracic volume dependence of the upper airway is most closely linked to the rib cage compartment level under the conditions of this study. The addition of one subject to the study since its original publication in abstract form (5) results in no changes in findings. Several mechanisms might link EELV to the degree of upper airway patency. Although upper airway muscles other than the genioglossus may mediate this effect, such a possibility is made much less likely by this study’s elimination of fluctuations in anterior nasal resistance and exclusion of laryngeal resistance and by animal studies demonstrating that multiple upper airway dilating muscles respond in a qualitatively similar fashion to phasic (31, 35) or sustained lung volume
ML
UC
(V) and for control
DC
periods (C), showing
change (19) and to vagotomy (31,35). However, given the absence of studies in humans that explore the effects of lung volume on the many upper airway muscles pertinent to supraglottic resistance, a role for upper airway constrictors or dissimilar responses by other upper airway dilators cannot be excluded in an explanation of the findings. The current protocol did not include the monitoring of pharyngeal mucosal blood volume, and as such the potential contribution of this factor (18) cannot be excluded. To the extent that increases in venous return may occur attendant to decreased intrathoracic pressure during inspiration in the VT range, such a mechanism is a plausible explanation for a relationship between lung volume and Ruaw. However, increased pulmonary vascular resistance at high lung volume (12) casts doubt on the degree to which this mechanism explains the current findings. Certainly, this concept is deserving of further study. It seems likely, however, that the effect*s of actively generated changes in EELV on Ruaw are mediated by linkages between the thorax and upper airway. Animal studies have suggested that tonic dilating
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UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND
LUNG
36.
EMtigeEu
* 3 .44 32,. 4 39 I 2 8-
435
VOLUME
LOW EELU
i-
I
P
--
HIGH EELU
l
Normalized MeanSEM
,
2 .6= 24. 1 . 2 29 4 2. I 1 .89 I 1 .6# 1 .4I 1 .2.
c
SUBJECT
u
RH
c
u
TC
c
u
ML
FIG. 3. Values for normalized end-expiratory genioglossal activity at high and low EELV periods (C), showing consistent increases at low and decreases at high EELV.
force is conveyed from the thorax to the upper airway by structures such as the trachea and neck muscles (1,30) and that the applied dilating force increases during actively mediated inspiration (1,27, 30-32). That the diaphragm simultaneously imparts collapsing and dilating force to the upper airway is strongly suggested by the observation that Ruaw increases during phrenic nerve stimulation in supine anesthetized dogs breathing through their upper airways (15); however, when negative inspiratory upper airway pressure is eliminated by the diversion of flow through a tracheostomy in a similar preparation (30), Ruaw decreases during phrenic stimulation. Interspecies differences make extrapolation to human disease difficult. However, by demonstrating that actively mediated changes in EELV induce changes in Ruaw not explained by genioglossal activity, the present study likewise suggests that, in humans, chest wall muscles may impart dilating force to the upper airway in addition to the more generally appreciated generation of collapsing force via negative inspiratory airway pressure (15, 26).
c
IJ
UC
c
U
DC
(V) and for control
That Ruaw and genioglossal activity are not inversely related in the present study cannot be taken to indicate the lack of a genioglossal role in the maintenance of upper airway patency. An extensive literature supports the concept of upper airway dilation and/or stabilization resulting from the activity of muscles intrinsic to the upper airway (2,3,14,15,20,22,23,26,29). Although the ability of upper airway muscles to dilate seems secure (14, 22, 29), whether an effect on elastance (stiffness) occurs or is clinically important seems less clear (14, 22). In the present study, the significant contribution of phasic genioglossal activity to changes in Guaw in a multiple linear regression model would be consistent with the genioglossus providing a phasic dilating influence. The specific mechanism(s) mediating the observed genioglossal responses to active sustained changes in EELV cannot be definitively determined from the present study. The immediacy of the genioglossal response (Fig. 1) and the lack of consistent changes in FETTER during these maneuvers (Table 2) exclude CO, perturba-
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436
UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND LUNG
VOLUME
4.2
LWJ EELU
+ P
--
HIGH EELU
4.0
1.4 Ruaw Normalized Mean~SEM
1.2
.8
.6
c
U
C
c
U
Rti TC SUWECT FIG. 4. Values for normalized Ruaw at high and low EELV increases at low and decreases at high EELV.
U
ML (V) and for control
tions as the causative factor. Given the persistence of the response to altered EELV over 20 breaths (Fig. l), it seems feasible that the response is vagally mediated (19, 35) by slowly adapting pulmonary stretch receptors. Alternatively, these responses would be consistent with an upper airway reflex response (20) to an alteration in load (change in resistance inducing change in pharyngeal pressure). Because the immediate genioglossal response to combined declines in EELV and pharyngeal pressure induced by continuous negative airway pressure is blunted by sleep (3), consciousness-dependent mechanisms may be involved in. these responses as either primary mechanisms or facilitators of one of the aforementioned reflexes, as proposed by Mathew et al. (20). However, recently reported preliminary data in two subjects suggest that similar genioglossal responses
U
c
UC
U
c
DC
periods (C), showing consistent
occur during sleep in response to elevations of EELV by negative extrathoracic pressure (6). The contrast between the present study and papers demonstrating no change in upper airway caliber (13) or dilating force (29) with passively increased EELV merits consideration. First, in the cited study of airway caliber, enough transrespiratory pressure was applied to increase EELV by the amount it had fallen during a shift from the seated to the supine position (248-855 ml). The active EELV changes in the present study were greater in magnitude and were thus more likely to demonstrate an effect based on passive mechanical factors. However, small increases (mean 0.53 liter) in EELV generated by an iron lung in sleeping humans have been reported to reduce total pulmonary resistance and Ruaw (6). Thus resistance, a functional measure, may be more
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UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND
LUNG
VOLUME
437
sensitive than averaged acoustic refl .ectance im ages in nohyoid length and passive tension, the relative ventral the assessmen t of small changes in the upper airw aY component vector of this tension will increase during that may occur during passively mediated changes in inspiration, potentially accounting for a greater degree EELV. Indeed, for actively mediated changes in lung of airway dilation. Similarly, decreases in ventrally divolume, altered upper airway caliber is demonstrated at rected passive force due to reductions in anteroposterior the extremes of lung volume (lo), whereas Ruaw tends diameter during deflation could result in increased airto demonstrate an inverse curvilinear relationship to way resistance. Second, muscle length does not necessarlung volume (7). The cited study of upper airway dilatily reflect the development of active tension in the antaging force in dogs (29) may have slhown no effect of pas- onistic suprahyoid and infrahyoid muscles (32), which sive volume change beca use of trachea 1 tran section results in a net ventral force applied to the hyoid arch (27,31-33). Finally, tracheal displacement (1,30) and its combined with small volume magnitude (30). The active mediation of the EELV change in the pres- relationship to RC EEL were not assessed in the current ent study prompts consideration that the tonic activastudy. tion of inspiratory chest wall muscles may have contribAs noted above, animal studies and the present data uted upper airway dilating force additional to that that may be interpreted as suggesting that the chest wall would have been associated with a similar increase in muscles simultaneously impart dilating and collapsing EELV achieved passively. Indeed, the lack of consistent forces to the up per airway. Th .us simple comparisons of changes in respiratory pattern (Table 2) suggests that chest wall and upper airw ‘aY muscle electromyograms may not accurately reflect the balance between upper increases in EELV were most likely achieved through airway collapsing and dilating forces. Rather, the net increases in tonic chest wall inspiratory activity rather mechanical effects of muscle activation must be considthan by dynamic hyperinflation. Deflation similarly was most likely mediated by tonic expiratory muscle ered. Indeed, progressive increases in supraglottic resisactivity. Various cervical accessory muscles such as the tance occur during the breaths preceding upper airway occlusion in the sleep apnea syndrome (26), despite a sternohyoid may function in an inspiratory capacity proportionate decline in diaphragmatic and genioglosand become active during large supratidal inspirations; thus it is likely that such muscular structures, which sal muscle electromyographic activities (23). Similarly, during periodic breathing induced by hypoxic gas mixmay dilate and stabilize the upper airway (1,27,30-34), developed active tension during the maneuvers to high tures and occurring at sleep onset, the wanes in the periEELV in the present study. The effects of such forces odic respiratory fluctuations are associated with inare not necessarily localized to the hypopharyngeal air- creases in airway resistance despite proportionate declines in diaphragmatic and genioglossal activities, as way; indeed, dilation of the rabbit oro- and nasopharynx has been observed to result from stimulation of the ster- assessed by esophageal and intramuscular electrodes, nohyoid or mechanical simulation of geniohyoid and respectively (4). These studies suggest that mechanical factors attendant to respiratory instability may faciligenioglossal activity (27). tate shifts in the balance between upper airway collapsIn the present study, subjects were allowed to determine spontaneously the specific thoracoabdominal con- ing and dilating forces despite similar fluctuations in figuration by which any given change in EELV was chest wall and upper airway muscle activation. Such findings may be explained by the following: -I>the proachieved. Ruaw proved to be more highly associated gressive withdrawal of phasic dilating forces imparted with changes in rib cage than abdominal compartmental volume. This observation presents an apparent para- by both the chest and upper airway muscles as their dox, in that the sternum and upper anterior rib cage phasic activation declines; 2) reductions in direct tonic elevate 2-4 cm by “pump handle” motion during inspiramuscular and/or passively transmitted dilating force as tion to total lung capacity in humans (24), thus ap- declines in EELV occur before upper airway occlusion in proaching the hyoid bone, which does not undergo con- sleep aP nea (2) and during the wanes of respiratory drive in peri .odic bre athing (4); 3) increases in the effisistent cephalad-caudad displacement during actively induced extremes of lung volume (1, 21). Sternohyoid ciency of negative inspiratory pressure generation as shortening with reduced passive tension in the cepha- inspiratory muscle length-tension relationships are aflad-caudad direction is implied. Similarly, sternal de- fected by declining EELV (2,25) and force-velocity relascent during reductions in RC EEL would be expected to tionships are affected by increasing Ruaw (25); and 4) nonconcurrent electromyogram quantification, because increase passive sternohyoid tension in the cephaladrespiratory electromyograms are commonly quantified caudad direction. Indeed, passive sternohyoid lengthening associated with sternal descent has been described as peak activity and a decrement in upper airway activin anesthetized eats (32), and such passive hyoid muscle ity generally occurs by the time of the diaphragmatic length changes have recently been implica #ted as able to peak (35). Thus, by providing evidence consistent with impart dilating force to the upper airway (34). Thus, the notion that chest wall muscles simultaneously imthese changes in passive tension would be expected to part both dilating and collapsing forces to the upper result in Ruaw changes opposite to those actually ob- airway in humans, these observations support the hyserved. Several explanations may be proposed. First, in- pothesis that sleep-related respiratory instability may spiratory “pump handle motion” is associated with an predispose to upper airway occlusion. Furthermore, increase in the anteroposterior dimension of the upper these concepts, together with the observation of a dechest (24); thus, regardless of the net change in ster- cline in FRC attendant to sleep (17), provide one explaI
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438
UPPER
AIRWAY
MUSCLE
ACTIVITY,
nation for the elevation of Ruaw during transition from wakefulness to sleep. In summary, it has been demonstrated that a dependence of Ruaw on actively generated changes in EELV occurs in supine humans, that this phenomenon is not mediated by genioglossus muscle activity, that changes in genioglossus activity appear to blunt the EELV-induced ehanges i n upper airway patency ., and that resistance is more cl osely linked to rib cage than abdominal end-expiratory position under the conditions of this study. It is thus suggested that muscular and/or passive linkages between the chest and the upper airway may mediate the th oracic volume dependence of Ruaw u nder the cond itions of this study. These resul ts suggest that fluctuations in EELV attendant to respiratory instability during sleep may predispose to upper airway occlu.
I
This study was supported by the Chicago Lung Association, the University of Illinois Campus Research Board, and the Medical Research Service of the Veterans Administration. Address for reprint requests: Robert M. Aronson, Pulmonary Office, Chicago College of Osteopathic Medicine, 20201 S. Crawford, Olympia Fields, IL 60461. Received 15 August 1989; accepted in final form 21 August 1990.
RESISTANCE,
displacement of the larynx: a study of the innervation of accessory respiratory muscles. J. Physiol. Lcmd. 130: 474-487,1955. 2. ARONSON, R. M., C. A. ALEX, E. i)lv~~, AND M. LOPATA. Changes in end-expiratory lung volume during sleep in patients with occlusive apnea. J. Appl. Physiot. 63: 1642-1647, 1987. 3, ARONSON, R. M., E. ONAL, D. W. CARLEY, AND M. LOPATA. Upper airway and respiratory muscle responses to continuous negative airway pressure. J. AppZ, Physiol. 66: 1373-1382, 1989. 4. ARONSON, R. M., E. ONAL, D. CARLEY, AND M. LOPATA. Changes in upper airway and respiratory muscle activity and pulmonary resistance during sleep-induced periodic breathing (Abstract). Am. Rev. Respir. Dis. 137, Suppk 126, 1988. 5. ARONSON, R. M., J. W&BORN, D. CARLEY, E. ONAL, AND M. LOPATA,
Effects of changes in end-expiratory lung volume on genioglossal activity and upper airway resistance (Abstract). Am. Rev. Respir. Dis. 139, Suppl: 450, 1989. 6. BEGLE, R. L., S. BADR, J. B. SKATRUD, AND J. A. DEMPSEY. Eflect of lung volume on pulmonary resistance during NREM sleep. Am. Rev. Respir. Dis. 141: 854-860,199O. 7. BLIDE, R. W., H. D. KERR, AND W. S. SPICER, JR. Measurement of
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AppL PhysioZ. 19: 1059-1069, 1964. 8. BRADLEY, T. D., I. G. BROWN, R. F. GROSSMAN, N. ZAMEL, D. MARTINEZ, E. A. PHILLIPSON, AND V, HOFFSTEIN. Pharyngeal size in
snorers, non-snorers, and patients with obstructive sleep apnea. N. Eq$. J. Med. 315: 1327-1331,1986. 9. BROWN, I. B., P. A. M&LEAN, R. BOUCHER, N. ZAMEL, AND V. HOFFSTEIN. Changes in pharyngeal cross-sectional area with posture and application of continuous positive airway pressure in patients with obstructive sleep apnea. Am. Rev. Respir+ Dis. 136: 628-632, 1987. 10. BROWN, I. B., N. ZAMEL, AND V. HOFFSTEIN. Pharyngeal cross-sectional area in normal men and women. J. Appl. Physiol. 61: 890895,1986. Il. CHADHA, T. S., H. WATSON, S. BIRCH, G. A. JENOURI, A. W. SCHNEIDER, M. A. COHN, AND M. A. SACKNER. Validation of respira-
tory inductive ptethysmography using different dures. Am. Rev. RestiT. LG. 125: 644-649.1982.
calibration
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12. CULVER, B. H., AND J. BUTLER. Mechanical influences on the pulmonary microcirculation. Annu. Rev. Physiol. 42: 187-198,198O. 13. FOUKE, J. M., AND K. P. STROHL. Elect of position and lung volume on upper airway geometry. J. AppZ. Physiol. 63: 375-380, 1987. 14. FOUKE, J. M., J. P. TEETER, AND K. P. STROHL. Pressure-volume behavior of the upper airway. J. Appl. Physiol. 61: 912-918,1986. 15. GOTTFRIED, S. B., K. S. STRQHL, W. B. VAN DE GRAAFF, J. M. FOUKE, AND A. F. DIMARCO. Effects of phrenic stimulation on upper airway resistance in anesthetized dogs. J, AppZ. Physiol. 55: 419-426,1983. 16. HOFFSTEIN, V., N. ZAMEL, AND E. A. PHILLIPSON. Lung volume de-
pendence of pharyngeal cross-sectional area in patients with obstructive sleep apnea. Am. Rev. Respir. Dis. 130: 175-178, 1984. 17. HUDGEL, D. W., AND P. DEVADATTA. Decrease in functional residual capacity during sleep in normal humans. J. Apph PhysioZ. 57: 1319-1322,1984. 18. Hum, D. A., M. J. WASICKO, R. A. PARISI, J. A. NEUBAUER, AND N. H. EDELMAN. Effects of vascular tone on pharyngeal size independent of skeletal muscle activity (Abstract). Am. Rev. Respir. LG. 139, Suppl: A374,1989. 19. ISCOE, STEVEN D. Central control of the upper airway. In: Respiratory Function of the Upper Airway, edited by 0. P. Mathew and G. Sant’Ambrogio. New York: Dekker, 1988, vol. 35, p. 125-192. (Lung
Biol. Health
Dis. Ser.) 0. P., Y. K. ABU-OSBA, AND B. T. THAGH. Influence of upper airway pressure changes on genioglossus muscle respiratory activity. Ji AppZ. Physiol 52: 438-444, 1982. MITCHINSON, A. G., AND J. M. YOFFEY. Respiratory displacement of larynx, hyoid bone and tongue. J. Anat. 81: 118-120,1947. OLSON, L. G., L. C. ULMER, AND N. A. SAUNDERS. Influence of muscle activity on the elastance of the upper airway of rabbits. J. Appb Physioh 66: 755-758, 1989. ONAL, E., J. LEECH, AND M. LOPATA. Dynamics of respiratory drive and pressure during NREM sleep in patients with occlusive apneas. J. AppZ. PhysioZ. 58: 1971-1974, 1985. OSMOND, D. G. Functional anatomy of the chest wall. In: The Thorax, edited by C. Roussos and P. T. Macklem. New York: Dekker, 1985, vol. 29, pt. A, p. 199-233. (Lung Biol. Health Dis. Ser.) PENGELLY, L. D., A. M. ALDERSON, AND J. MILIC-EMUII. Mechanics of the diaphragm. J. AppZ. PhysioE. 30: 797-805,197l. REMMERS, J. E., W. J. DEGROOT, E. K. SAUERLAND, AND A. M. ANCH. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol. 44: 931-938, 1978. ROBERTS, J. L., W. R. REED, AND B. T. THACH. Pharyngeal airway stabilizing function of sternohyoid and sternothyroid muscles in the rabbit. J. AppZ. Physiol. 57: 1790-1795,1984. SPANN, R. W., AND R. E. HYATT. Factors affecting upper airway resistance in conscious man. J. AppZ. Physiol. 31: 708-712, 1971. STROHL, K. P., AND J. M. FOUKE. Dilating forces on the upper airway of anesthetized dogs. J. AppZ. Physiol. 58: 452-458,1985. VAN DE GRAAFF, W. B. Thoracic influence on upper airway patency. J. AppZ. Physiol. 65: 2124-2131, 1988. VAN DE GRAAFF, W. B,, S. B. GOTTFRIED, J. MITRA, E. VAN LUNTEREN, N. S. CHERNIACK, AND K. P. STROHL. Respiratory function of hyoid muscles and hyoid arch. J. AppZ. Physiol. 57: 197-204,
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1984. 32. VAN LUNTEREN, E., M. A. HAXHIQ
AND N. S. CHERNIACK. Mechanical function of hyoid muscles during spontaneous breathing in cats. J. AppZ. Physiol. 62: 582-590, 1987. 33. VAN LUNTEREN, E., M. A. HAXHIU, AND N. S. CHERNIACK. Relation between upper airway volume and hyoid muscle length. J. AppZ. Physiol. 63: 1443-1449, 1987. 34. VAN LUNTEREN, E., M. A. HAXHIU, AND N. S. CHERNIACK. Reflex effects of preventing lung inflation on hyoid muscle length and upper airway volume (Abstract). Am. Rev. Respir. Dis. 139, SuppZ: 446,1989. 35. VAN LUNTEREN, E., K. STROHL, D. M. PARKER, E. N. BRUCE, W. B. VAN DE GRAAFF, AND N. S. CHERNIACK. Phasic volume-related feedback on upper airway muscle activity. J. AppZ. Physiol. 56: 730-736.1984.
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and the thuracic
volume
dependence
of upper
airway
re-
sistance. J. Appl. Physiol. 70(l): 430-438, 1991.-Although a thoracic volume dependence of upper airway resistance and caliber is known to exist in seated subjects, the mechanisms mediating this phenomenon are unknown. To test the hypothesis that actively altered end-expiratory lung volume (EELV) affects upper airway resistance in the supine position and to explore the mechanisms of any EELV-induced resistance changes, we studied five normal males during wakefulness. Supraglottic upper airway resistance (Ruaw) was calculated at an inspiratory flow of 0.1 l/s. The genioglossal electromyogram was obtained with indwelling wire electrodes and processed as moving time average. End-tidal CO, was monitored by infrared analyzer. Observations were made during four 20breath voluntary maneuvers: two at high and two at low EELV in each subject. Each maneuver was preceded by a control period at functional residual capacity. At high lung volume the EELV was increased by 2.23 t 0.54 (SD) liters; Ruaw decreased to 67.8 zt 35.1% of control, while tonic and phasic genioglossal activities declined to 79.0 r4 23.1 and 72.4 t 29.8%) respectively. At low lung volume the EELV was decreased by 0.86 t 0.23 l’t1 ers. Ruaw increased to 178.2 -t 186.8%, while tonic and phasic genioglossal activities increased to 243.0 t 139.3 and 249.1 t 146.3%, respectively (P < 0.0001 for all). The findings were not explained by COz perturbations or respiratory pattern. Multiple linear regression analysis indicated that the genioglossal responses blunted the EELV-induced changes in upper airway patency. We conclude that actively mediated increases in EELV in the supine position are associated with reduced Ruaw, decreases in EELV are associated with increased Ruaw, and genioglossal activity is not the means by which these relationships occur. The generation of tension in muscles linking the thorax to the upper airway and/ or the transmission of force via the trachea may explain the
observations. These findings suggest that fluctuations in EELV attendant
to respiratory
instability
during
sleep may
predispose to upper airway occlusion. genioglossal electromyogram; occlusive apnea; upper airway occlusion; sleep apnea; end-expiratory lung volume; functional residual capacity
PREVIOUS WORK from our laboratory
breath-to-breath 430
fluctuations
demonstrated that in end-expiratory lung
0161-7567/91
$1.50 Copyright
volume (EELV) occur during the cyclic breathing characteristic of obstructive sleep apnea (2). However, little is understood about the relationship of changes in lung volume to upper airway patency. An association between upper airway caliber and actively mediated changes in thoracic volume has been described in seated obese and nonobese normal subjects (8, 10, 16) and in seated obese and nonobese patients with obstructive sleep apnea (8, 16). Similarly, an inverse relationship between upper airway resistance (Ruaw) and actively mediated changes in EELV has been described in seated normal subjects (28). Whether similar relationships would persist during actively induced lung volume changes in supine humans is not known. The means by which the thoracic volume dependence of upper airway patency occurs is unknown. It has been speculated that this phenomenon may occur through the activity of upper airway dilating muscles (8-10, 16), which theoretically would be stimulated concurrently with the inspiratory muscles by linked brain stem motoneurons (16) or influenced by inflation reflexes (8-10, 16). However, the validity of this explanation has never been specifically examined. Next, pharyngeal mucosal blood volume, which has been shown to affect upper airway caliber (18), may be affected by hemodynamic shifts resulting from lung volume changes. Finally, the thoracic volume dependence of upper airway patency may occur through mechanical linkages between the thorax and upper airway. Recent work by Van de Graaff (30) has strongly supported the hypothesis that such mechanical linkages mediate declines in Ruaw during activation of thoracic inspiratory muscles in supine tracheotomized dogs. This work demonstrated that declines in Ruaw occurred during spontaneous inspiration, during inspiration induced by phrenic nerve stimulation in apneic animals, and during spontaneous inspiration in animals with upper airway denervation; elimination of inspiratory declines in Ruaw required the transection of all ventrolateral cervical structures. In obstructive sleep apnea, the breath-by-breath fluctuations in EELV occur during spontaneous breathing (with thoracic inspiratory muscle activation) and generally in the recumbent position. Thus we proceeded to
0 1991 the American
Physiological
Society
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UPPER
DC ML RH VC TC
32 47 32 30 28
Mean st SD
34-+8
AIRWAY
180.3 167.6 180.3 185.4 182.9 179.3t6.9
MUSCLE
73.2 58.2 74.1 84.1 69.1 71.7k9.4
ACTIVITY,
111.2 116.7 85.7 87.5 107.5 101.7t14.2
RESISTANCE, AND LUNG VOLUME
120.2 110.4 98.4 93.1 106.4 105.7t10.5
FE&, forced expiratory volume in 1 s; FVC, forced vital capacity; FRC, functional Ruaw, upper airway resistance during pooled control periods (means t SD).
assess whether actively mediated alterations in EELV affect Ruaw in supine humans and explored the mechanisms of any such phenomenon by the concomitant measurement of upper airway muscle activity.
76.1 80.9 72.2 79.6 85.2
residual
78.8t4.9
capacity measured
431
116.1 92.2 104.5 81.2 118.8 102.6t15.9
3.5k2.2 7.7t3.3 3.5tl.5 2.5tl.6 1.6tl.O 3.8k2.9
by body plethysmography;
Five normal nonsnoring male volunteers were studied after they signed an informed consent form approved by the Institutional Review Board of the University of Illinois at Chicago. The subjects were of normal body weight and were free of pulmonary disease (Table 1). A tight-fitting nasal mask (Respironics, Monroeville, PA) was worn by all subjects. Tidal volume (VT) and inspiratory flow were measured by a pneumotachograph (Fleisch no, 3, Hewlett-Packard 47303A) in four subjects and by a IO-liter water seal spirometer (Warren E. Collins, Braintree, MA) in one subject. Inspiratory and expiratory durations (TI and TE, respectively) were measured from the flow tracing. Minute ventilation (VI) was calculated from VT, TI, and TE. Inspiratory pressure across the supraglottic upper airway was assessed by a balloon-tip catheter positioned by use of endoscopic guidance at the tip of the epiglottis and referenced to mask pressure by a Gould-Statham differential transducer (PMlSlTC). Multiple holes were created in the distal catheter to ensure accurate transmission of pressure to the catheter lumen. Splints were placed in the nostrils to prevent changes in anterior nasal resistance. The catheter emerged from the nose through a splint and was secured with tape to prevent migration. Inspiratory Ruaw was calculated at a flow of 0.1 l/s (4). End-tidal CO, was monitored by infrared analyzer (Beckman LB-Z) with a sampling cannula placed in one of the nasal splints. Genioglossal electromyography was performed with bilateral indwelling wire electrodes (platinum-1076 iridium alloy) placed perorally. The signal was amplified, band-passed (30-600 Hz), rectified, moving time averaged (Paynter filter, 0.1 s time constant), and quantified as both phasic inspiratory change from expiratory baseline (EMGge) and “tonic” expiratory activity measured from electrical zero (EMGgeEEL). Direct current-coupled respiratory inductive plethysmography (Respitrace, Ardsley, NY) was used to measure the changes in EELV (2,3). The coils were taped to the thorax and abdomen in a nonbinding manner to pre-
squares (11), and validation to prove accuracy to within tlO% of simultaneous spirometry over a wide range of relative rib cage and abdominal contributions to VT was performed in all subjects. The stability of coil position was confirmed at the conclusion of each study. All subjects were studied in the supine position. The inductive plethysmograph sum signal was displayed on an oscilloscope that the subjects viewed by mirror, facilitating the maintenance of a given EELV. The pneumotachograph VT tracing was not used for this purpose because the device incorporated separate potentiometers for inspiratory and expiratory calibration; small differences in these calibrations appear as shifts in EELV over time. Observations were made during four maneuvers (two 20-breath periods at both high and low EELVs) in each subject. The EELVs obtained were determined empirically as the highest and lowest end-expiratory volumes that the subjects could comfortably maintain without visible thoracic spine or neck flexion. On the basis of data associating changes in respiratory pattern with alterations in Ruaw (28), during the maneuvers to high and low EELV, we required that the subjects attempt to superimpose the sum signal over a drawing of the resting pattern, which was traced to the oscilloscope screen during the ZOobreath control period that preceded each maneuver. Overall reasonable consistency was noted in raw EMGgeEEL and EMGge mean values between the four control periods (respective coefficients of variation 9.3, 11.6,11.5,71.6, and 24.7 and 16.9,22.2,6.1,15.9, and 28.5% in subjects VC, RH, TC, ML, and DC; the value of 71.6% occurred in the only subject undergoing electrode replacement in midstudy). However, one-way analysis of variance (ANOVA) performed for each subject revealed the differences between control periods to be statistically significant (P c 0.01) for both parameters (except EMGge in subject TC, P > 0.30). We thus chose to normalize to pool data. The breath-by-breath values for EMGge, EMGgeEEL, Ruaw, VT, VI, TI, and TEwere divided by their respective mean values during the control period that preceded each maneuver. Breath-by-breath values for the changes in rib cage, abdominal, and summated end-expiratory levels from their respective mean control period positions were recorded (ARC EEL, AAB EEL, and ASUM EEL, respectively). In addition, the change in exhaled CO, fraction (FET,,,) from the control period mean was calculated on a breath-by-breath
vent
basis during
METHODS
slippage.
Calibration
was by the method
of least
each maneuver.
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432
UPPER
AIRWAY
TABLE 2. Changes in FETED,, Tr, TE, low end-expiratory lung volumes Subj
MUSCLE VT,
ACTIVITY,
RESISTANCE,
AND
LUNG
VOLUME
I%, RC EEL, AB EEL, and SUM EEL at high and
A F’ET~~ Composition, %
A TI,
ATE,
AVT,
Air I,
ARC EEL,
%
%
%
%
liters
A AB EEL, liters
A SUM EEL, liters
0.03t0.43 0.26t0.37
1.7k20.3 -24.Ok24.8
-6.4-1-26.2 4.8k23.3
-14.9t27.2 -23.4k25.3
2.22kO.22 -0.43t0.14
-0.05t0.38 -0.17+0.15
2.17t0.45 -0.60t0.12
-0.OhO.25 0.33t0.33
16.5k23.3 17.1k24.8
-10.8t24.5 -26.7t20.6
-24.9t16.2
-2.7t23.1 -18.3-1-17.4
1.55t0.10 -0.65t0.13
0.51t0.10 -0.30t0.05
2.06t0.12 -0.94t0.13
O.llt0.28 -0.29~~0.17
28.Ok29.9 11.7k29.5
2.4t31.1 -10.6k22.3
28.2t21.7 18.0t13.8
15.6t23.5 19.9t20.3
l.llt0.32 -0.41t0.26
0.43t0.17 -0.62t0.10
1.54t0.26 -1.02t0.22
-1.00+0*19 -0.66t0.20
18.3_+30.0 -1.ot19.1
-3.6t20.0 18.8t31.9
31.0t23.9 22.5t28.3
25.7229.2 13.4-t-46.9
1.93kO.47 -1.04t0.18
0.62t0.15 0.27t0.09
2.54t0.45 -0.77t0.14
0.06t0.25 -0.17t0.14
1.0+14.3 1.4kl6.7
16.8t20.6 6.8t14.0
-3.8t11.2 13.0t12.2
1.43-+0.x3 -0.44t0.14
1.35t0.13 -0.55t0.23
2.77t0.28 -0.99xk0.19
-0.lW0.52 -0.14t,o.44
12.8k26.2 O.Ok27.1
-0.5t26.2 O.lt27.4
1.67~~0.48 -0.59t0.30
0.56kO.50 -0.27t0.36
2.2320.54 -0.86t0.23
RH
H L
-19.2t18.5 -29.5t25.1
TC
H L
-2.Ot15.9
ML
H L VC H
L DC H L Pooled H L
Values are means + SD of changes from preceding control
6.6-t-27.2 1.21k30.0
-10.9-tl4.5 8.9tl6.6 2.7k28.7 1.3t32.9
period. H, high end-expiratory
The statistical significance and reproducibility of changes in EMGge, EMGgeEEL, and Ruaw during the maneuvers to high and low EELV were assessed by twoway repeated measures ANOVA. The stability of Ruaw, EELV, EMGge, EMGgeEEL, and FETED, during the course of the 20-breath maneuvers at high and low lung volume was evaluated by one-way ANOVA. Finally, because the results did not demonstrate an inverse relationship between genioglossal activity and Ruaw (see RESULTS), we utilized a multiple regression analysis to investigate whether the alterations in EMGge and EMGgeEEL may have served to blunt the EELV-associated changes in upper airway patency. Although the protocol did not include graded EELV changes in individual subjects, the pooled observations contained a wide range of volumes above and below supine functional residual capacity (FRC) (Table 2). The relationship between Ruaw and lung volume in individual subjects has been shown to be inverse and curvilinear, creating a linear relationship between upper airway conductance (Guaw) and lung volume (7). Thus Guaw (l/raw Ruaw, 1 s-l l cmH,O-I) was used as the dependent variable in the multiple linear regression analysis. l
RESULTS
Ruaw during all control periods was 3.8 t 2.9 (SD) cmH,O .l-1 4s-l (Table 1). During maneuvers to high volume, EELV was increased by 2.23 t 0.54 liters (range 1.54 t 0.26 to 2.77 t 0.28; Table 2). Phasic and end-expiratory genioglossal activity declined (Figs. l-3) to 72.4 + 28.9 and 79.0 t 23.1% of control, respectively. Despite the declines in genioglossal activity, Ruaw at high EELV fell to 67.8 t 35.1% of control (Fig. 4). During maneuvers to low volume, EELV was decreased by 0.86 t 0.23 liter (range 0.60 t 0.12 to 1.02 t 0.22; Table 2). Phasic and end-expiratory genioglossal activity increased (Figs. l-3) to 249.1 t 146.3 and 243.0 t 139.3% of
lung volume; L, low end-expiratory
lung volume.
control, respectively. Despite the increases in genioglossal activity, Ruaw at low EELV increased to 178.2 t 186.8% of control (Fig. 4). The changes in Ruaw, EMGge, and EMGgeEEL were highly significant during maneuvers to both high and low EELV (P c 0.0001 for all). No statistically significant effect of first vs. second trial was noted for Ruaw or EMGge during maneuvers to high EELV or for EMGgeEEL during maneuvers to low EELV. The significant trial effects noted for EMGgeEEL (P < 0.004, high EELV) and Ruaw and EMGge (P < 0.0005 and 0.0001, low EELV) were due to quantitative rather than qualitative differences, Similarly, although obvious intersubject variability was present, it was overwhelmingly quantitative rather than qualitative in nature (Figs. 2-4). In contrast to the qualitative consistency of the genioglossal and resistance responses, the changes in endtidal CO, and respiratory pattern during high and low EELV periods were inconsistent (Table 2). Although significant increases in TI were noted in three of the five subjects during maneuvers to high EELV, no consistent overall trends to increases or decreases in TI, TE, VT, VI, or end-tidal CO, were otherwise noted during maneuvers to either high or low EELV (Table 2). Thus, although individual subjects demonstrated deviation from their resting respiratory patterns despite the aid of visual feedback, there was no overall consistency to the pattern of this deviation. No significant changes in Ruaw, EELV phasic or endexpiratory genioglossal activity, or FET,,, were noted for the group over the course of the 209breath maneuvers at either high or low lung volume (P > 0.56 for all). The inclusion of ASUM EEL, EMGge, and EMGgeEEL as independent variables in a multiple linear regression revealed that ASUM EEL and EMGge each made significant independent contributions to the changes in Guaw (P < 0.0001 and 0.0004, respectively) such that Guaw increased with increases in lung volume
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UPPER AIRWAY MUSCLE ACTIVITY, RESISTANCE, AND LUNG VOLUME
433
LMGge
EMGge
I I1.5
uT hh
-
60
SEC.
-
FIG. 1. Tracings of genioglossal electromyogram (EMGge), spirogram (VT), and expired CO2 (FET~~J during maneuvers to high (t@ and low (bottom) end-expiratory lung volumes. Obvious declines of phasic and end-expiratory genioglossal activity occur at high EELV, and increases occur at low EELV. These changes in EMGge are not explained by changes in FETED,.
and phasic genioglossal activity. The substitution of ARC EEL and AAB EEL for ASUM EEL in the analysis revealed that the contribution of lung volume to Guaw was explained by the changes in ARC EEL (P < O.OOOl), whereas AAB EEL added no significant independent contribution to the model. Because we measured changes from supine FRC rather than absolute supine lung volumes, and because intersubject differences in upper airway caliber have been related to differences in body surface area and lung volume (lo), the multiple regression analysis was repeated with Guaw normalized to its control period mean, with Guaw divided by absolute seated FRC, and with the lung volume changes nor-
malized to seated FRC. In each instance, phasic genioglossal activity and the changes in lung volume each made significant independent positive contributions to Guaw, with the lung volume contribution always being through the rib cage compartment. DISCUSSION
This study demonstrates that significant decreases in supraglottic resistance and genioglossus muscle activity occur with actively mediated increases in EELV in supine normal subjects. Similarly, significant increases in resistance and genioglossus activity occur with active
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434
UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND
LUNG
VOLUME
+ P
LOUJ IEEtlJ --HIGH
EELU
3.67 4 3.4. 4 3.2.
EMGge
, 39 I 2%
Normalized
2.6* 2.49 I 2.2. , 2. 1.8= 4 1 .6. 4 1.4m
.6 .4
SUBJECT
RH
TC
2. Values for phasie genioglossal activity at high and low EELV consistent increases at low and decreases at high EELV. FIG.
reductions in EELV. Thus an inverse relationship between Ruaw and actively generated changes in EELV has been confirmed in supine humans. Furthermore, it has been shown that this phenomenon is not mediated by genioglossus muscle activity. Multiple linear regression analysis indicates that the genioglossus muscle responses act to blunt the EELV-induced changes in upper airway patency. Finally, the thoracic volume dependence of the upper airway is most closely linked to the rib cage compartment level under the conditions of this study. The addition of one subject to the study since its original publication in abstract form (5) results in no changes in findings. Several mechanisms might link EELV to the degree of upper airway patency. Although upper airway muscles other than the genioglossus may mediate this effect, such a possibility is made much less likely by this study’s elimination of fluctuations in anterior nasal resistance and exclusion of laryngeal resistance and by animal studies demonstrating that multiple upper airway dilating muscles respond in a qualitatively similar fashion to phasic (31, 35) or sustained lung volume
ML
UC
(V) and for control
DC
periods (C), showing
change (19) and to vagotomy (31,35). However, given the absence of studies in humans that explore the effects of lung volume on the many upper airway muscles pertinent to supraglottic resistance, a role for upper airway constrictors or dissimilar responses by other upper airway dilators cannot be excluded in an explanation of the findings. The current protocol did not include the monitoring of pharyngeal mucosal blood volume, and as such the potential contribution of this factor (18) cannot be excluded. To the extent that increases in venous return may occur attendant to decreased intrathoracic pressure during inspiration in the VT range, such a mechanism is a plausible explanation for a relationship between lung volume and Ruaw. However, increased pulmonary vascular resistance at high lung volume (12) casts doubt on the degree to which this mechanism explains the current findings. Certainly, this concept is deserving of further study. It seems likely, however, that the effect*s of actively generated changes in EELV on Ruaw are mediated by linkages between the thorax and upper airway. Animal studies have suggested that tonic dilating
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UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND
LUNG
36.
EMtigeEu
* 3 .44 32,. 4 39 I 2 8-
435
VOLUME
LOW EELU
i-
I
P
--
HIGH EELU
l
Normalized MeanSEM
,
2 .6= 24. 1 . 2 29 4 2. I 1 .89 I 1 .6# 1 .4I 1 .2.
c
SUBJECT
u
RH
c
u
TC
c
u
ML
FIG. 3. Values for normalized end-expiratory genioglossal activity at high and low EELV periods (C), showing consistent increases at low and decreases at high EELV.
force is conveyed from the thorax to the upper airway by structures such as the trachea and neck muscles (1,30) and that the applied dilating force increases during actively mediated inspiration (1,27, 30-32). That the diaphragm simultaneously imparts collapsing and dilating force to the upper airway is strongly suggested by the observation that Ruaw increases during phrenic nerve stimulation in supine anesthetized dogs breathing through their upper airways (15); however, when negative inspiratory upper airway pressure is eliminated by the diversion of flow through a tracheostomy in a similar preparation (30), Ruaw decreases during phrenic stimulation. Interspecies differences make extrapolation to human disease difficult. However, by demonstrating that actively mediated changes in EELV induce changes in Ruaw not explained by genioglossal activity, the present study likewise suggests that, in humans, chest wall muscles may impart dilating force to the upper airway in addition to the more generally appreciated generation of collapsing force via negative inspiratory airway pressure (15, 26).
c
IJ
UC
c
U
DC
(V) and for control
That Ruaw and genioglossal activity are not inversely related in the present study cannot be taken to indicate the lack of a genioglossal role in the maintenance of upper airway patency. An extensive literature supports the concept of upper airway dilation and/or stabilization resulting from the activity of muscles intrinsic to the upper airway (2,3,14,15,20,22,23,26,29). Although the ability of upper airway muscles to dilate seems secure (14, 22, 29), whether an effect on elastance (stiffness) occurs or is clinically important seems less clear (14, 22). In the present study, the significant contribution of phasic genioglossal activity to changes in Guaw in a multiple linear regression model would be consistent with the genioglossus providing a phasic dilating influence. The specific mechanism(s) mediating the observed genioglossal responses to active sustained changes in EELV cannot be definitively determined from the present study. The immediacy of the genioglossal response (Fig. 1) and the lack of consistent changes in FETTER during these maneuvers (Table 2) exclude CO, perturba-
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436
UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND LUNG
VOLUME
4.2
LWJ EELU
+ P
--
HIGH EELU
4.0
1.4 Ruaw Normalized Mean~SEM
1.2
.8
.6
c
U
C
c
U
Rti TC SUWECT FIG. 4. Values for normalized Ruaw at high and low EELV increases at low and decreases at high EELV.
U
ML (V) and for control
tions as the causative factor. Given the persistence of the response to altered EELV over 20 breaths (Fig. l), it seems feasible that the response is vagally mediated (19, 35) by slowly adapting pulmonary stretch receptors. Alternatively, these responses would be consistent with an upper airway reflex response (20) to an alteration in load (change in resistance inducing change in pharyngeal pressure). Because the immediate genioglossal response to combined declines in EELV and pharyngeal pressure induced by continuous negative airway pressure is blunted by sleep (3), consciousness-dependent mechanisms may be involved in. these responses as either primary mechanisms or facilitators of one of the aforementioned reflexes, as proposed by Mathew et al. (20). However, recently reported preliminary data in two subjects suggest that similar genioglossal responses
U
c
UC
U
c
DC
periods (C), showing consistent
occur during sleep in response to elevations of EELV by negative extrathoracic pressure (6). The contrast between the present study and papers demonstrating no change in upper airway caliber (13) or dilating force (29) with passively increased EELV merits consideration. First, in the cited study of airway caliber, enough transrespiratory pressure was applied to increase EELV by the amount it had fallen during a shift from the seated to the supine position (248-855 ml). The active EELV changes in the present study were greater in magnitude and were thus more likely to demonstrate an effect based on passive mechanical factors. However, small increases (mean 0.53 liter) in EELV generated by an iron lung in sleeping humans have been reported to reduce total pulmonary resistance and Ruaw (6). Thus resistance, a functional measure, may be more
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UPPER
AIRWAY
MUSCLE
ACTIVITY,
RESISTANCE,
AND
LUNG
VOLUME
437
sensitive than averaged acoustic refl .ectance im ages in nohyoid length and passive tension, the relative ventral the assessmen t of small changes in the upper airw aY component vector of this tension will increase during that may occur during passively mediated changes in inspiration, potentially accounting for a greater degree EELV. Indeed, for actively mediated changes in lung of airway dilation. Similarly, decreases in ventrally divolume, altered upper airway caliber is demonstrated at rected passive force due to reductions in anteroposterior the extremes of lung volume (lo), whereas Ruaw tends diameter during deflation could result in increased airto demonstrate an inverse curvilinear relationship to way resistance. Second, muscle length does not necessarlung volume (7). The cited study of upper airway dilatily reflect the development of active tension in the antaging force in dogs (29) may have slhown no effect of pas- onistic suprahyoid and infrahyoid muscles (32), which sive volume change beca use of trachea 1 tran section results in a net ventral force applied to the hyoid arch (27,31-33). Finally, tracheal displacement (1,30) and its combined with small volume magnitude (30). The active mediation of the EELV change in the pres- relationship to RC EEL were not assessed in the current ent study prompts consideration that the tonic activastudy. tion of inspiratory chest wall muscles may have contribAs noted above, animal studies and the present data uted upper airway dilating force additional to that that may be interpreted as suggesting that the chest wall would have been associated with a similar increase in muscles simultaneously impart dilating and collapsing EELV achieved passively. Indeed, the lack of consistent forces to the up per airway. Th .us simple comparisons of changes in respiratory pattern (Table 2) suggests that chest wall and upper airw ‘aY muscle electromyograms may not accurately reflect the balance between upper increases in EELV were most likely achieved through airway collapsing and dilating forces. Rather, the net increases in tonic chest wall inspiratory activity rather mechanical effects of muscle activation must be considthan by dynamic hyperinflation. Deflation similarly was most likely mediated by tonic expiratory muscle ered. Indeed, progressive increases in supraglottic resisactivity. Various cervical accessory muscles such as the tance occur during the breaths preceding upper airway occlusion in the sleep apnea syndrome (26), despite a sternohyoid may function in an inspiratory capacity proportionate decline in diaphragmatic and genioglosand become active during large supratidal inspirations; thus it is likely that such muscular structures, which sal muscle electromyographic activities (23). Similarly, during periodic breathing induced by hypoxic gas mixmay dilate and stabilize the upper airway (1,27,30-34), developed active tension during the maneuvers to high tures and occurring at sleep onset, the wanes in the periEELV in the present study. The effects of such forces odic respiratory fluctuations are associated with inare not necessarily localized to the hypopharyngeal air- creases in airway resistance despite proportionate declines in diaphragmatic and genioglossal activities, as way; indeed, dilation of the rabbit oro- and nasopharynx has been observed to result from stimulation of the ster- assessed by esophageal and intramuscular electrodes, nohyoid or mechanical simulation of geniohyoid and respectively (4). These studies suggest that mechanical factors attendant to respiratory instability may faciligenioglossal activity (27). tate shifts in the balance between upper airway collapsIn the present study, subjects were allowed to determine spontaneously the specific thoracoabdominal con- ing and dilating forces despite similar fluctuations in figuration by which any given change in EELV was chest wall and upper airway muscle activation. Such findings may be explained by the following: -I>the proachieved. Ruaw proved to be more highly associated gressive withdrawal of phasic dilating forces imparted with changes in rib cage than abdominal compartmental volume. This observation presents an apparent para- by both the chest and upper airway muscles as their dox, in that the sternum and upper anterior rib cage phasic activation declines; 2) reductions in direct tonic elevate 2-4 cm by “pump handle” motion during inspiramuscular and/or passively transmitted dilating force as tion to total lung capacity in humans (24), thus ap- declines in EELV occur before upper airway occlusion in proaching the hyoid bone, which does not undergo con- sleep aP nea (2) and during the wanes of respiratory drive in peri .odic bre athing (4); 3) increases in the effisistent cephalad-caudad displacement during actively induced extremes of lung volume (1, 21). Sternohyoid ciency of negative inspiratory pressure generation as shortening with reduced passive tension in the cepha- inspiratory muscle length-tension relationships are aflad-caudad direction is implied. Similarly, sternal de- fected by declining EELV (2,25) and force-velocity relascent during reductions in RC EEL would be expected to tionships are affected by increasing Ruaw (25); and 4) nonconcurrent electromyogram quantification, because increase passive sternohyoid tension in the cephaladrespiratory electromyograms are commonly quantified caudad direction. Indeed, passive sternohyoid lengthening associated with sternal descent has been described as peak activity and a decrement in upper airway activin anesthetized eats (32), and such passive hyoid muscle ity generally occurs by the time of the diaphragmatic length changes have recently been implica #ted as able to peak (35). Thus, by providing evidence consistent with impart dilating force to the upper airway (34). Thus, the notion that chest wall muscles simultaneously imthese changes in passive tension would be expected to part both dilating and collapsing forces to the upper result in Ruaw changes opposite to those actually ob- airway in humans, these observations support the hyserved. Several explanations may be proposed. First, in- pothesis that sleep-related respiratory instability may spiratory “pump handle motion” is associated with an predispose to upper airway occlusion. Furthermore, increase in the anteroposterior dimension of the upper these concepts, together with the observation of a dechest (24); thus, regardless of the net change in ster- cline in FRC attendant to sleep (17), provide one explaI
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438
UPPER
AIRWAY
MUSCLE
ACTIVITY,
nation for the elevation of Ruaw during transition from wakefulness to sleep. In summary, it has been demonstrated that a dependence of Ruaw on actively generated changes in EELV occurs in supine humans, that this phenomenon is not mediated by genioglossus muscle activity, that changes in genioglossus activity appear to blunt the EELV-induced ehanges i n upper airway patency ., and that resistance is more cl osely linked to rib cage than abdominal end-expiratory position under the conditions of this study. It is thus suggested that muscular and/or passive linkages between the chest and the upper airway may mediate the th oracic volume dependence of Ruaw u nder the cond itions of this study. These resul ts suggest that fluctuations in EELV attendant to respiratory instability during sleep may predispose to upper airway occlu.
I
This study was supported by the Chicago Lung Association, the University of Illinois Campus Research Board, and the Medical Research Service of the Veterans Administration. Address for reprint requests: Robert M. Aronson, Pulmonary Office, Chicago College of Osteopathic Medicine, 20201 S. Crawford, Olympia Fields, IL 60461. Received 15 August 1989; accepted in final form 21 August 1990.
RESISTANCE,
displacement of the larynx: a study of the innervation of accessory respiratory muscles. J. Physiol. Lcmd. 130: 474-487,1955. 2. ARONSON, R. M., C. A. ALEX, E. i)lv~~, AND M. LOPATA. Changes in end-expiratory lung volume during sleep in patients with occlusive apnea. J. Appl. Physiot. 63: 1642-1647, 1987. 3, ARONSON, R. M., E. ONAL, D. W. CARLEY, AND M. LOPATA. Upper airway and respiratory muscle responses to continuous negative airway pressure. J. AppZ, Physiol. 66: 1373-1382, 1989. 4. ARONSON, R. M., E. ONAL, D. CARLEY, AND M. LOPATA. Changes in upper airway and respiratory muscle activity and pulmonary resistance during sleep-induced periodic breathing (Abstract). Am. Rev. Respir. Dis. 137, Suppk 126, 1988. 5. ARONSON, R. M., J. W&BORN, D. CARLEY, E. ONAL, AND M. LOPATA,
Effects of changes in end-expiratory lung volume on genioglossal activity and upper airway resistance (Abstract). Am. Rev. Respir. Dis. 139, Suppl: 450, 1989. 6. BEGLE, R. L., S. BADR, J. B. SKATRUD, AND J. A. DEMPSEY. Eflect of lung volume on pulmonary resistance during NREM sleep. Am. Rev. Respir. Dis. 141: 854-860,199O. 7. BLIDE, R. W., H. D. KERR, AND W. S. SPICER, JR. Measurement of
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AppL PhysioZ. 19: 1059-1069, 1964. 8. BRADLEY, T. D., I. G. BROWN, R. F. GROSSMAN, N. ZAMEL, D. MARTINEZ, E. A. PHILLIPSON, AND V, HOFFSTEIN. Pharyngeal size in
snorers, non-snorers, and patients with obstructive sleep apnea. N. Eq$. J. Med. 315: 1327-1331,1986. 9. BROWN, I. B., P. A. M&LEAN, R. BOUCHER, N. ZAMEL, AND V. HOFFSTEIN. Changes in pharyngeal cross-sectional area with posture and application of continuous positive airway pressure in patients with obstructive sleep apnea. Am. Rev. Respir+ Dis. 136: 628-632, 1987. 10. BROWN, I. B., N. ZAMEL, AND V. HOFFSTEIN. Pharyngeal cross-sectional area in normal men and women. J. Appl. Physiol. 61: 890895,1986. Il. CHADHA, T. S., H. WATSON, S. BIRCH, G. A. JENOURI, A. W. SCHNEIDER, M. A. COHN, AND M. A. SACKNER. Validation of respira-
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Dis. Ser.) 0. P., Y. K. ABU-OSBA, AND B. T. THAGH. Influence of upper airway pressure changes on genioglossus muscle respiratory activity. Ji AppZ. Physiol 52: 438-444, 1982. MITCHINSON, A. G., AND J. M. YOFFEY. Respiratory displacement of larynx, hyoid bone and tongue. J. Anat. 81: 118-120,1947. OLSON, L. G., L. C. ULMER, AND N. A. SAUNDERS. Influence of muscle activity on the elastance of the upper airway of rabbits. J. Appb Physioh 66: 755-758, 1989. ONAL, E., J. LEECH, AND M. LOPATA. Dynamics of respiratory drive and pressure during NREM sleep in patients with occlusive apneas. J. AppZ. PhysioZ. 58: 1971-1974, 1985. OSMOND, D. G. Functional anatomy of the chest wall. In: The Thorax, edited by C. Roussos and P. T. Macklem. New York: Dekker, 1985, vol. 29, pt. A, p. 199-233. (Lung Biol. Health Dis. Ser.) PENGELLY, L. D., A. M. ALDERSON, AND J. MILIC-EMUII. Mechanics of the diaphragm. J. AppZ. PhysioE. 30: 797-805,197l. REMMERS, J. E., W. J. DEGROOT, E. K. SAUERLAND, AND A. M. ANCH. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol. 44: 931-938, 1978. ROBERTS, J. L., W. R. REED, AND B. T. THACH. Pharyngeal airway stabilizing function of sternohyoid and sternothyroid muscles in the rabbit. J. AppZ. Physiol. 57: 1790-1795,1984. SPANN, R. W., AND R. E. HYATT. Factors affecting upper airway resistance in conscious man. J. AppZ. Physiol. 31: 708-712, 1971. STROHL, K. P., AND J. M. FOUKE. Dilating forces on the upper airway of anesthetized dogs. J. AppZ. Physiol. 58: 452-458,1985. VAN DE GRAAFF, W. B. Thoracic influence on upper airway patency. J. AppZ. Physiol. 65: 2124-2131, 1988. VAN DE GRAAFF, W. B,, S. B. GOTTFRIED, J. MITRA, E. VAN LUNTEREN, N. S. CHERNIACK, AND K. P. STROHL. Respiratory function of hyoid muscles and hyoid arch. J. AppZ. Physiol. 57: 197-204,
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