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John Rankin Laboratory of Pulmonary Medicine, Department of Preventive Medicine, University of Wisconsin, Madison, Wisconsin 53705
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Curran, Aidan K., Peter R. Eastwood, Craig A. Harms, Curtis
A. Smith, and Jerome A. Dempsey. Superior laryngeal nerve section
alters responses to upper airway distortion in sleeping dogs.
J. Appl. Physiol. 83(3): 768-775, 1997.
We investigated the effect of superior laryngeal nerve (SLN)
section on expiratory time
(TE) and genioglossus
electromyogram (EMGgg) responses to upper airway (UA) negative pressure
(UANP) in sleeping dogs. The same dogs used in a similar intact study
(C. A. Harms, C. A., Y.-J. Zeng, C. A. Smith, E. H. Vidruk, and J. A. Dempsey. J. Appl. Physiol. 80:
1528-1539, 1996) were bilaterally SLN sectioned. After recovery,
the UA was isolated while the animal breathed through a tracheostomy.
Square waves of negative pressure were applied to the UA from below the
larynx or from the mask (nares) at end expiration and held until the
next inspiratory effort. Section of the SLN increased eupneic
respiratory frequency and minute ventilation. Relative to the same dogs
before SLN section, sublaryngeal UANP caused less
TE prolongation while activation of the genioglossus required less negative pressures. Mask UANP had no
effect on TE or EMGgg activity.
We conclude that the SLN 1) is not
obligatory for the reflex prolongation of
TE and activation of EMGgg
activity produced by UANP and 2)
plays an important role in the maintenance of UA stability and the
pattern of breathing in sleeping dogs.
negative pressure; control of breathing; upper airway muscles; electromyogram
INTRODUCTION UPPER AIRWAY (UA) negative pressure (UANP) has been
shown to alter the pattern of breathing in anesthetized dogs (4, 29) and rabbits (14, 15) and in awake and sleeping dogs (5, 8, 16). In
general, these effects were a prolongation of inspiratory duration
(TI), although a prolongation
of expiration duration (TE)
has also been reported in some instances (5, 15, 16). In
addition to timing effects, UANP has also been shown to stimulate
genioglossus (GG) muscle electromyogram (EMGgg) activity in
anesthetized dogs (29) and rabbits (11-13, 15) and in awake and
sleeping dogs (5, 8, 16) as well as to increase phrenic and hypoglossal
nerve activity in decerebrate cats (7).
The superior laryngeal nerve (SLN) is the primary afferent innervation
of the larynx and contains a substantial number of receptors sensitive
to airway pressure (2, 24). Section of the SLN has been shown to reduce
or abolish the inhibition of breathing due to UANP applied to the
larynx in anesthetized dogs (29) and rabbits (15) and to reduce or
abolish the EMGgg activation secondary to UANP in anesthetized dogs
(29) and rabbits (11, 12, 15).
Recently, Harms et al. (5) demonstrated a substantial prolongation of
TE and an increase in tonic
EMGgg activity in response to negative pressure applied to the isolated
UA at end expiration in awake and sleeping dogs. The prolongation of
TE became apparent only after
the airway collapsed and increased as more negative pressure was
applied to the collapsed airway. This effect was independent of whether
the pressure was applied from below the larynx or from the face mask.
This indicates that the SLN may not be the primary afferent arm of this
reflex because the pressure applied to the UA via the mask would not be
transmitted to the larynx after UA collapse, yet the prolongation of
TE was still correlated with the
applied negative pressure. Also, because topical anesthesia of the UA,
which abolished all responses to water and ammonia, failed to abolish
the response, Harms et al. reasoned that, because surface-receptor
output had been abolished, it was the distortion of deeper structures
in the UA after collapse had occurred that produced the responses seen.
There is evidence that the SLN contains fibers that innervate deeper
structures in the vicinity of the epiglottis (26). Such receptors
provide a potential pathway for the response to UANP and would likely
be unaffected by topical airway anesthesia. The purpose of the present
study was to examine what role, if any, the SLN plays in the reflex responses to UANP as reported by Harms et al.
METHODS Animal Instrumentation
For the purpose of this study, similar techniques were used to perform
a second sterile surgery to denervate the SLNs. A ventral midline
incision was made in the neck, and the SLNs were exposed bilaterally
and cut close to their insertion on the vagus nerves. At least 2 wk
were allowed for recovery before experiments. SLN section was confirmed
before commencement of experiments by the absence of a gag reflex due
to mechanical probing of the larynx and the instillation of saline or
distilled water into the larynx via the sublaryngeal catheter (Fig.
1). The surgical and experimental protocols
of this study were approved by the Animal Care and Use Committee of the
University of Wisconsin.
Ventilation and EMGs
The dogs were intubated with a cuffed tracheostomy tube (12.0 mm OD) via the tracheostomy (Fig. 1). The tracheostomy tube was connected to a heated pneumotachograph and pressure transducer system (Hans Rudolph 3700, Kansas City, MO; Validyne MP-45-14-871, Northridge, CA). Calibration was performed before each experiment by using five known flow rates. EMGgg and costal diaphragm EMG activities were amplified, rectified, and moving time averaged with a time constant of 100 ms (CWE, Ardmore, PA).Isolation of the UA
The UA was isolated by sealing both around the mask and below the larynx (Fig. 1). A tight-fitting lightweight plastic face mask was fitted to the dogs face and lined with a gel-polymer sheath that provided an airtight seal around the dog's snout. This mask ensured that the dogs were unable to open their mouths, and thus UANP applied at the mask was transmitted to the UA only via the nose. A balloon-tipped catheter was then inserted rostrally into the tracheostomy above the tracheostomy tube to lie just caudal to the cricoid cartilage. Inflation of the balloon produced an isolated UA (Fig. 1). This catheter as well as a second catheter inserted through the face mask to lie near the nares were connected to pressure transducers (Validyne) and used to simultaneously measure mask and sublaryngeal pressures. These transducers were calibrated before each experiment by application of eight known pressures. Application of negative pressure to the isolated UA was achieved by using a syringe connected to either the sublaryngeal or the mask catheter.Experimental Protocol
The dogs were trained to sleep on a bed in an air-conditioned, sound-attenuated chamber while wearing the face mask and tracheostomy apparatus. Dogs were unrestrained and allowed to choose their own posture. The dogs' behavior was monitored by using a closed-circuit television camera.Once a stable breathing pattern was observed during quiet wakefulness
or non-rapid-eye-movement (NREM) sleep, UANP trials were performed with
at least a 2-min interval between each trial. Trials consisted of the
application of a square wave of negative pressure to the isolated UA
via either the sublaryngeal catheter or the mask catheter late in
expiration and the maintenance of the pressure until the beginning of
the next inspiratory effort (Fig. 2).
Multiple trials were performed with pressures ranging from 
1 to
32 cmH2O.
, tracheal airflow. A: note
prolongation of expiratory duration when pressure in sublaryngeal area
is made negative beyond point of UA collapse indicated by plateau of
pressure trace in mask at approximately 4
cmH2O. Note also activation of
genioglossus with UA negative pressure applied from below larynx.
B: note lack of expiratory duration
prolongation as well as genioglossus activation with UA negative
pressure applied from mask despite UA collapse, indicated by plateau of
Psl trace at 4 cmH2O. Also
observe that Pm trace crosses Psl
trace as it becomes more negative.
Sleep Staging
Standard canine sleep staging criteria were used to identify sleep stage (22). NREM sleep was defined as a slow-wave EEG without associated rapid eye movements. An EEG arousal was defined as desynchronous EEG activity for >3 s. Any trials where there was evidence of arousal were excluded from further analysis.UA Closure
During trials in sleep, the pressure at which the mask and sublaryngeal pressures diverged during the application of UANP was defined as the closing pressure (Fig. 2). To estimate the site of UA closure, a terminal study was performed in two of the dogs. After anesthesia with pentobarbital sodium, the dogs were instrumented for application of UANP as described in Ventilation and EMGs. In addition, a third catheter was inserted through the nose and passed down to the level of the larynx. This catheter was also connected to a pressure transducer (Validyne). Application of negative pressure from either the mask or sublaryngeal catheter could be measured in the third catheter. This catheter was withdrawn 1 cm at a time, and collapsing pressures were applied from the mask and sublaryngeal catheters. By measuring the resultant pressure deflection in the third catheter and noting any deviation from the pressure applied, we were able to determine whether this catheter was in communication with the area above or below the site of collapse. By this method we were able to estimate the site within the UA at which collapse occurred in each case.Data Collection and Analysis
All signals were recorded on a 12-channel polygraph (Gould ES 2000, Rolling Meadows, IL) and were passed through an analog-to-digital converter and stored on the hard disk of a microcomputer for later analysis using a software package developed in house. All signals were sampled at 64 Hz. The software calculated ventilatory variables breath by breath from the flow signal. Each dog acted as its own control. For the purpose of statistical comparison, the data presented here for the SLN-intact dogs are redrawn from the data of Harms et al. (5). Statistical comparisons of the eupneic values for ventilatory variables for and the closing pressures between SLN-intact and SLN-sectioned dogs were performed by using unpaired Student's t-tests. Analysis of covariance was used to examine the effect of UANP on TE between SLN-intact and SLN-sectioned dogs as well as between UANP applied at the mask and from below the larynx. Differences between groups were tested by using both linear and quadratic terms. In all cases, P < 0.05 was considered significant.RESULTS
NREM
Effect of SLN section on eupneic ventilation. Section of the SLN produced a marked alteration of the pattern of eupneic ventilation in all three dogs during NREM sleep (Table 1). After section, control values for respiratory frequency and minute ventilation increased significantly in all three dogs (27 and 31% for respiratory frequency and minute ventilation, respectively, for the 3 dogs combined). The effect on respiratory frequency was due to reductions in both inspiratory and expiratory durations (30 and 12% respectively). Tidal
volume was generally unaffected, with only dog
2 showing a significant increase.
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4
cmH2O. This plateau signifies that
the pressure being applied from below the larynx is no longer being
transmitted to the mask, indicating that the UA has collapsed. Notice
also after the collapse the prolongation of
TE and the increase in the level
of tonic EMGgg activity.
Application of negative pressure to the isolated UA from below the
larynx during NREM sleep in SLN-intact dogs at end expiration produced
a marked prolongation of TE.
This increase in TE was dose
dependent with a threshold for prolongation at approximately 8
cmH2O and a maximal effect at
30 cmH2O (Fig.
3). The term threshold refers to the fact
that application of pressures above 8
cmH2O in the SLN-intact dogs
failed to produce a response, whereas more negative pressures caused
TE prolongation. After SLN
section, application of negative pressure to the UA from below the
larynx still caused a significant increase in
TE in all three dogs during NREM
sleep. After section of the SLN, a threshold for
TE prolongation was not as
evident as in the intact animals because of the greater scatter in the
data. In each dog, however, the response to UANP applied from below the
larynx was slightly but significantly less than that seen in the same
animal before section of the SLN (Fig. 3).
) or SLN sectioned (
). SLN-intact data are replotted from Harms et al. (5). Lines are best fit
by using linear or squared terms.
UANP APPLIED FROM THE MASK. An example of the response to UANP applied at the mask after SLN section is shown in Fig 2B. Notice that, in this case, UA collapse resulted in a plateau in the sublaryngeal pressure trace at approximately
4cmH2O and that there was
no effect on TE or EMGgg
activity.
The effect of UANP applied at the mask is shown in Fig. 3. When UANP
was applied from the mask during NREM sleep in the SLN-intact dogs,
TE was increased to the same
extent as that seen with UANP applied from below the larynx. However,
after SLN section, there was no effect of UANP applied at the mask on
TE in any of the three dogs.
Effect of SLN section on the GG response to UANP.
An example of the activation of the GG by UANP is shown in Fig.
2A. The response of the
GG to UANP is shown for all dogs in Table
2. In the SLN-intact animals the incidence of
GG activation by UANP was greater as the negative pressure applied
became more negative. This effect was independent of the route of
application of the negative pressure. After SLN section, EMGgg activity
was still increased by UANP applied from below the larynx during NREM sleep. The pattern of activation was similar to that reported for the
SLN-intact dogs, namely the greater the negative pressure applied the
greater the frequency of GG activation. Notice, however, that after SLN
section there was a greater incidence of GG activation in the pressure
range between 4 and 15
cmH2O (14, 25, and 0% of trial
for each dog with intact SLN vs. 33, 75, and 100% after section,
respectively).
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8
cmH2O during NREM sleep. This was not significantly different from the collapsing pressure when the UANP
was applied from the mask (Fig. 4). After section of the SLN, the
collapsing pressure was approximately
4cmH2O (Figs. 2,
A and
B, and 4), with no significant
difference between the collapsing pressure between UANP applied at the
mask or from below the larynx.
) and after (
)
section of the SLN. SLN-intact data are replotted from data of Harms et
al. (5).
In two of the dogs, the area in the UA where closure occurred due to UANP was measured under anesthesia by using a third, moveable airway catheter (see METHODS). In these trials a negative pressure of approximately
20
cmH2O was applied to the UA to
ensure collapse. Collapse occurred at approximately 4
cmH2O (or 20% of the pressure
applied). Pressures were applied from below the larynx and from the
mask. The results are shown schematically in Fig.
5, A and
B. These results indicate that the
nasopharynx collapsed over a region measuring 5-7 cm stretching
from the base of the soft palate rostrally toward the base of the hard
palate (Fig. 5A). This is a
substantially larger area than that reported for one of the dogs before
section of the SLN (5), where the site of collapse appeared to be over
a region not larger than 2 cm, stretching from the base of
the soft palate upward (see Fig.
5A).
20
cmH2O was applied, first from
below larynx and then from mask. Difference between area of collapse before and after section of SLN is shown schematically in sagittal section. Solid line, area of collapse in intact dog; dashed line, area
of collapse in 2 dogs after SLN section.
B: representations of pressure
measured in third mobile catheter, during study in anesthetized dogs,
expressed as percentage of pressure applied below larynx (solid line)
or at mask (dotted line) at each level. When airway collapses between
catheter and point of pressure application, pressure measured in
catheter will plateau at approximately 4 cmH2O, or 20% of pressure
applied. Accordingly, distance between point at which catheter pressure
deviated from sublaryngeal pressure and point where it begins to
reflect pressure applied at mask is area over which airway collapsed.
Wakefulness
Application of UANP during wakefulness was only possible in two of the dogs after SLN section because of the overt behavioral responses of dog 1 to application of any pressure more negative than10
cmH2O. During wakefulness in the
other two dogs, results were very variable. Both dogs showed
TE prolongation and EMGgg activation in response to UANP applied from below the larynx of similar
magnitude to that reported during sleep. Application of UANP from the
mask during wakefulness, however, produced a
TE prolongation similar to that
seen with UANP applied from below the larynx, while only one of the
dogs showed an increase in EMGgg activity with UANP applied at the
mask.
Because of these variations and the overt behavioral effects, we do not believe that the use of the awake state permitted us to properly evaluate the effect of SLN section per se on the effect of UANP on breathing and EMGgg activity.
It may be the case that SLN section produced a more prevalent behavioral response during wakefulness because of some conscious sensation associated with collapse of the airway over a larger area.
DISCUSSION
The main findings from this study are as follows. 1) Section of the SLN alters the pattern of breathing in tracheostomized, sleeping dogs by means of an increase in respiratory frequency and minute ventilation. 2) The SLN is not required for either the TE prolongation or the increase in EMGgg activity produced by UANP applied from below the larynx in sleeping dogs, because the response is still present after section. 3) Section of the SLN, however, does lead to the abolition of both the TE prolongation and the EMGgg activation due to UANP applied at the mask during NREM sleep. This is likely because section of the SLN produced a more widespread UA collapse such that UANP applied at the mask failed to stimulate the presumably more caudal receptive field responsible for both the TE prolongation and the increase in EMGgg activity.
Effect of SLN Section on Eupneic Ventilation
The effect of SLN section on eupneic ventilation has been studied in conscious adult rats (19), neonatal kittens (20), and neonatal guinea pigs (3). In the conscious rats and kittens, the authors reported an increase in respiratory frequency and minute ventilation with no effect on tidal volume, although only the effect on frequency was significant in the rats and with neither increase significant in the kittens. These results are similar to those reported here in the unanesthetized, sleeping dogs. In awake neonatal guinea pigs SLN section resulted in a significant reduction in respiratory frequency and minute ventilation with no effect on tidal volume (3). This difference may reflect a different role of the SLN in the neonatal vs. adult animals.It is important to note that the dogs in this study were breathing via a tracheostomy and thus were without most of the normal feedback from UA afferents in the SLN even during the SLN-intact experiments. Accordingly, the feedback from temperature receptors and other receptors active during eupneic airflow were absent, and the only afferent activity in the SLN would be from "drive receptors" (24), which are responsive to mechanical stimuli such as tracheal tug (27) and which would still provide some feedback in the absence of airflow. Such receptors have been described as naked nerve endings in the airway muscle; they act like spindles (10) and have activity that can persist even after topical airway anesthesia (9). The absence of this feedback after SLN section would appear to be the source of the alteration in the pattern of breathing after SLN section. Indeed, this is consistent with the lack of effect of topical airway anesthesia on the pattern of breathing in the intact dogs (5) which would only affect the surface receptors. The increase in respiratory frequency after SLN section may reflect an inhibitory effect of these deeper mechanoreceptors on eupneic ventilation. Increasing the activity of these receptors by negative pressure application may then be expected to inhibit frequency further, leading to an apnea. The reduction in the TE prolongation in response to airway distortion after SLN section is likely to be due to loss of the afferent innervation of these deeper receptors. The remaining TE prolongation and EMGgg activation after SLN section is likely to be due to similar receptors elsewhere in the airway that are carried in other nerves such as the glossopharyngeal or trigeminal nerves, the relative importance of which remains to be determined.
One might expect that SLN section in animals breathing through the UA would have a much larger effect on the pattern of eupneic breathing because there would be even greater SLN activity associated with eupneic airflow. Similarly, the SLN, although not obligatory for the TE prolongation and EMGgg activation associated with UANP, plays an important role in the regulation of the pattern of eupneic ventilation through the presence of a respiratory-related feedback.
Effect of SLN section on EMGgg Activity and UA Closure
SLN section has been shown to abolish the effect of UANP applied from below the larynx on EMGgg activity in the anesthetized rabbit (11). After SLN section, EMGgg activation due to UANP applied from below the larynx was still present but was absent when UANP was applied at the mask. The difference in the results between this study and the rabbit study may be due to the presence of anesthesia in the rabbit model, because anesthesia has been shown to reduce or abolish UA reflexes (6).UANP has also been shown to increase hypoglossal nerve activity in decerebrate, paralyzed, ventilated cats (7). In that study, SLN section reduced, but did not abolish, the increased hypoglossal activity due to UANP, whereas the response was increased by glossopharyngeal section and abolished by trigeminal section. Thus other UA afferents are responsive to UANP and may provide the afferent pathway for the prolongation of TE and EMGgg activation seen. However, the exact route of afferent transduction has yet to be investigated in sleeping animals.
Our findings demonstrate that section of the SLN reduced the level of negative pressure required for UA collapse and appeared to increase the area over which the UA collapses. There is evidence that the muscles of the soft palate increase their activity in response to UANP applied from below the larynx in anesthetized dogs (28) and that this effect is SLN mediated (21). Indeed, section of the SLN in anesthetized dogs has been shown to reduce the tonic activity of palatine muscles (21). Such an effect on either palatine or other UA muscles, for example, pharyngeal constrictors, would be expected to destabilize the nasopharynx and could explain the reduced negative pressure required to collapse the UA as well as the increase in the area of airway collapse in the SLN-sectioned dogs. This could result in UA collapse at a site too rostral to stimulate the receptive field responsible for the reflex prolongation of TE and EMGgg activation. The precise area and form of such an alteration in site of collapse, however, could only be demonstrated by direct visualization of the UA.
Mechanism of TE Prolongation
Negative pressure stimulates receptors through distortion of the cytoskeleton in the surrounding microenvironment. Previous studies have shown an increase in TE due to UANP applied during expiration in anesthetized rabbits (15) and in dogs during wakefulness (16). In the anesthetized rabbit studies, Mathew and Farber (15) reported that UANP applied during expiration caused a significant prolongation of TE. However, they did not document whether the UA had collapsed, although their laboratory (12) has previously reported that the airway in the anesthetized rabbit collapses spontaneously. The authors of the awake dog study (16), on the other hand, reported no prolongation of TE with UANP applied during expiration. In that study, McNamara et al. (16) did not report the stage of expiration during which the pressure was applied. Our studies in the intact dogs demonstrates that the airway is more resistant to collapse during early expiration and that UANP applied early in expiration had no significant effect on TE. These data may suggest that one only sees the TE prolongation when the negative pressure is sufficient to cause a substantial airway distortion.Obviously, the intensity and duration of the stimulus are critical determinants of the response produced. The TE prolongation and EMGgg activation reported here required a sufficient level of negative pressure to stimulate receptors that require some level of airway distortion to be activated. This is evident from the correlation between the TE prolongation and UA collapse demonstrated in the SLN-intact study (5) and with the fact that abolition of surface-receptor activity with topical anesthesia of the airway failed to affect the response (5). In the awake dog study performed by McNamara et al. (16), the pressure applied during expiration failed to cause TE prolongation. This may have been because the airways were less compliant during wakefulness or because the negative pressure may have been applied early in expiration when the airway is more resistant to distortion (5). The anesthetized rabbit model did show a TE prolongation with UANP applied during expiration, but in this case it is likely that the airway was already collapsed (12) and accordingly was more susceptible to the distorting effect of UANP on deeper receptors.
It is important to note that our distinction between negative pressure and distortion is not to imply a lack of an effect of UANP but rather to distinguish between local distortion of surface receptors usually associated with UANP and the shearing forces acting on muscle spindles and drive receptors located deeper in the UA musculature that can only be affected by more pronounced distortion of the airway.
As with the effect of UANP on EMGgg activation, we believe that SLN section increases the compliance of the UA such that UANP application produces collapse at a site too cranial to produce TE prolongation. This destabilization appears to be due to the removal of the activity of drive receptors because application of a lidocaine solution, which abolished all surface-receptor activity while having less effect on drive receptors (25), had no effect on the TE prolongation response in the intact dogs (5). The prolongation of TE associated with UANP applied from below the larynx is likely due to inputs carried in other UA afferents that remain to be determined. These afferents may be either muscle spindles or naked nerve endings similar to the drive receptors supplied by the SLN (23).
Relevance
The presence of the TE prolongation and EMGgg activation reflexes during the expiratory phase may be of interest considering data in sleeping humans that demonstrate that the airway can close even during a central apnea (1). The airway distortion associated with this collapse may act to prolong the apnea. Indeed, recent evidence has shown that the airway narrows progressively during the expiratory phase in the breaths leading to a central apnea (17, 18). This progressive expiratory narrowing in the absence of UANP is associated with increasing expiratory durations (23) and may be part of a cycle of airway wall stretch due to passive airway narrowing leading to longer expiratory durations, which allow further narrowing ultimately leading into an apnea.ACKNOWLEDGEMENTS
We are grateful for the assistance of Laurel Finn for advice on statistical analysis of the data. We also thank Kathy Henderson for technical assistance.
FOOTNOTES
Address for reprint requests: A. K. Curran, University of Wisconsin, Dept. of Preventive Medicine, 504 N. Walnut St., Madison, WI 53705 (E-mail: acurran{at}facstaff.wisc.edu).
Received 4 December 1996; accepted in final form 7 April 1997.
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