| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Desmond N. Stoker Sleep Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H3A 1A1
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Cala, S. J., P. Sliwinski, M. G. Cosio, and R. J. Kimoff.
Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea. J. Appl.
Physiol. 81(6): 2618-2626, 1996.
It has
previously been reported that the duration of obstructive apneas
increases from the beginning to the end of the night (M. Charbonneau,
J. M. Marin, A. Olha, R. J. Kimoff, R. D. Levy, and M. Cosio.
Chest 106: 1695-1701, 1994
[Abstract]
). The purpose of this study was
to test the hypothesis that stimulation of upper airway (UA) sensory
receptors during obstructed inspiratory efforts contributes to arousal
and apnea termination and that a progressive attenuation of this
mechanism through the night contributes to apnea lengthening. We
studied seven patients (six men, one woman) with severe obstructive
sleep apnea (apnea-hypopnea index = 93 ± 26 events/h) during two
consecutive nights of polysomnographic monitoring. On one night (random
order), we performed topical UA anesthesia with 0.2% tetracaine and on
the control night, sham anesthesia. We measured apnea duration,
esophageal pressure (Pes) during apneas, and apneic
O2 desaturation. Consistent with
previous findings, apnea duration, number of efforts per apnea, and
peak Pes at end apnea increased from the beginning to the end of the control nights. UA anesthesia produced a significant increase in apnea
duration at the beginning of the night but no change in apnea length at
the end of the night. Peak Pes and the rate of increase in Pes during
the anesthesia nights were greater than during control nights, but the
rate of increase in Pes was similar for the beginning and end of the
control and anesthesia nights. These findings suggest that UA sensory
receptors play a role in mediating apnea termination at the beginning
of the night but that the contribution of these receptors diminishes as
the night progresses such that greater inspiratory efforts are
required to trigger arousal, leading to apnea prolongation.
arousal; pharynx; pleural pressure; tetracaine; upper airway
mechanoreceptors
INTRODUCTION IN OBSTRUCTIVE SLEEP APNEA (OSA), upper airway (UA)
occlusion during sleep is typically associated with increasing
inspiratory efforts against the obstructed UA. The reestablishment of
UA patency requires arousal, thought to be a response to afferent
stimulation related to the UA occlusion (23, 26, 30). Previous work has
also shown in OSA patients that afferent mechanoreceptor stimuli produced during obstructed inspiratory efforts play an important role
in mediating arousal and apnea termination (15). There are
also data to suggest that mechanical stimulation of the UA may be
involved in the arousal response to UA occlusion (1, 2, 14, 20).
It has recently been shown that the duration of obstructive apneas
increases from the beginning to the end of the night (6) and that this is associated with an increase in the level of
inspiratory effort at end-apnea (15, 21). If the UA is involved in
determining apnea termination by conveying feedback of mechanical
stimulation, apnea prolongation could be explained by a diminution in
sensory function through the night. This could be because of injury
resulting from repeated mechanical trauma due to UA obstruction
throughout the night, leading to an increase in the level of mechanical
stimulation required to trigger arousal.
In the light of these findings, we hypothesized that
1) UA mechanoreceptors play an
important role in the arousal response to UA obstruction in OSA; and
2) a progressive attenuation of UA
mechanoreceptor function through the night requires a greater level of
inspiratory effort to produce arousal, leading to an increase in apnea
duration. To test this, we compared apnea duration, inspiratory effort,
and O2 saturation
(SaO2) after sham and true UA
anesthesia (An; administered on anesthesia night) when both were
administered at the beginning and the end of the night. We predicted
that inhibition of UA sensory receptor function by anesthesia at the
beginning of the night should produce apnea prolongation of similar
magnitude to that previously reported at the end of the night (27). In
contrast, when anesthesia was administered through the night we
expected apnea duration to either remain constant or increase
minimally.
METHODS One female and six male subjects with untreated OSA confirmed by
polysomnography were recruited from the Royal Victoria Hospital Sleep
Clinic (Montreal). All subjects underwent routine testing of pulmonary
function in the department's laboratory. The subjects were taking no
regular medications and had no other active medical problems. The study
was approved by the Human Ethics Committee of the Royal Victoria
Hospital, and written informed consent was obtained from all subjects.
There were eight other subjects enrolled in the study whose results
were incomplete or could not be used in the final analysis. Three
subjects were unable to tolerate the esophageal catheter, and four
subjects could not maintain a constant posture throughout both nights.
In addition, one subject failed to return for a second night's study.
Each subject underwent two consecutive nights of full overnight
polysomnography. A balloon-tipped esophageal catheter was placed for
pleural pressure [measured as esophageal pressure (Pes)] measurements. The catheter was connected to a differential pressure transducer (Validyne P300D). The balloon volume (0.6 ml) was repeatedly verified throughout the night. Insertion of the catheter was assisted by 1-2 ml of 4% lidocaine viscous solution. Catheter placement was performed before the polysomnographic instrumentation to allow the
maximum time for the effects of the lidocaine to diminish before stage
2 sleep on the control night. The time elapsed between catheter
placement and lights out ranged from 70 to 90 min. Rib cage and
abdominal motion were monitored by respiratory inductance plethysmography (Respitrace, Ardsley, NY). Airflow was measured by
using an oronasal thermistor. Body position was monitored by continuous
infrared video surveillance. Sleep stage and arousals were identified
according to standard criteria (25). Apnea was defined as complete
cessation of airflow (>90% reduction compared with baseline) for at
least 10 s and hypopnea as a >50% reduction in flow for at least 10 s. Virtually all events analyzed terminated in association with an
arousal pattern on the electroencephalograph and electromyograph (25).
All of the above parameters were recorded continuously on a polygraph
recorder (model 78D, Grass Instruments, Quincy, MA) and simultaneously
onto a personal computer by using a data-acquisition program (CODAS,
DATAQ Instruments, Akron, OH).
Data analysis. A given sleep period was eligible for analysis if it met the following criteria: 1) it was within the first hour after lights out; 2) it was during established stage 2 non-rapid-eye-movement (NREM) sleep (allowing for end-apneic microarousals) at least 10 min before or after a rapid-eye-movement (REM) period; and 3) the subject was in the same posture (supine or side lying) for all recording periods. These criteria were chosen to assess the effect of tetracaine anaesthesia during its expected peak activity and to avoid spurious changes in apnea characteristics because of changes in posture and sleep stage. In addition, to minimize the risk of postural changes occurring after the 1-h period of data acquisition influencing the subsequent recordings, we required subjects to remain in the same position all night, resulting in the exclusion of four subjects because of difficulties in maintaining posture. Although data were acquired for 1 h after lights out during the first (C1, An1) and second (C2, An2) periods of the night, we also required that the subjects sleep continuously throughout, except for being awakened at C2 and An2 by the operator and spontaneously at night's end. The latter was required in view of the hypothesis that any changes in the measured parameters from the beginning to the end of the night were associated with the effects of continuous sleep. Ten consecutive apneas were analyzed within each period by a single operator blinded to the experimental condition. The following measurements were made: 1) apnea duration (
t), defined as
the time between the start of the first obstructed effort to the
resumption of airflow; 2) number of
apneic efforts; 3) baseline and
end-apneic oxyhemoglobin O2
saturation (SaO2); 4) rate of
O2 desaturation
(SaO2/t);
and 5) peak Pes just before arousal
(Pespeak). We also
calculated the rate of increase of effort
(Pes/t) during apneas, as
previously described (15, 21). In this study we also calculated the
mean increase in the peak inspiratory pressure per effort
(Pes/efforts) and the rate of apneic efforts
(efforts/t). Finally, we also
calculated an apnea-hypopnea index (AHI; events/h) for the four
analysis periods that were used to compare apnea severity between the
diagnostic polysomnography night and the control and anesthesia nights.
Statistical analysis.
We used a two-way analysis of variance (ANOVA) based on 10 apneas/subject to test for statistical significance of differences in
the number of apneic efforts,
Pespeak, and peak and nadir
SaO2 among C1, C2, An1, and An2. Because
Pes/t, Pes/efforts,
efforts/t, and
Sa O2/t were
derived and results for t were not normally distributed, to test for differences in these values we used
Friedman's test for multiple comparisons and Wilcoxon's signed-rank
test for post hoc paired comparisons (with adjustment of the level of
significance by the Bonferroni correction for multiple comparisons). A
P < 0.05 was accepted as
significant.
RESULTS
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
) and esophageal pressure (Pes) for obstructed
efforts and 1st postapneic breath for typical apneas in stage 2 sleep
during each of 4 experimental periods. Note that apnea duration
increases from C1 to C2. However, apnea duration at An1 and An2 is same and comparable to apnea length for C2. Note increase in peak Pes before
arousal from C1 to C2. Note also peak Pes before arousal and rate of
change of inspiratory effort for anesthetic compared with control
events are increased.
The group mean data for apnea duration are shown in Fig. 3. Apnea duration increased by 31 ± 5 (SE) % from C1 to C2 (P = 0.0001; Fig. 3), similar to previous findings (6, 21). At the beginning of the night, oropharyngeal anesthesia resulted in apnea lengthening (An1 25 ± 5% >C1, P < 0.001), the extent of which was comparable to the lengthening of events across the control nights (An1 and C2 were not significantly different, P > 0.4). In contrast, UA anesthesia at the end of the night produced little effect on apnea duration (i.e., An2 was not significantly different from An1 or C2).
The data for inspiratory effort during apneas are summarized in Table 3. During control nights, the number of efforts per apnea increased from C1 to C2 (P < 0.001; Table 3). At An1, although there was a trend for an increase in the number of efforts per apnea compared with C1, during the anesthesia night this failed to reach statistical significance (P = 0.08). The maximal apneic effort increased by 42 ± 8% at C2 relative to C1 (P = 0.0001; Table 3) and by 105 ± 15% at An1 (P = 0.0001) compared with C1. When compared with that at C2, maximal apneic effort at An2 was 42 ± 6% greater (P = 0.0001) but was not different from that at An1 (P = 0.8). The rate of change of inspiratory effort (
Pes/t) was
substantially increased during both An1 and An2 compared with C1 and C2
(P = 0.001). The increase in the rate
of change of inspiratory effort between control and anesthesia periods
was entirely explained by an increase in Pes/efforts with no change
in efforts/t
(P = 0.09).
|
||||||||||||||||||||||||||||||||||||||||||||||||
SaO2/t
was higher during An1 (P = 0.001)
compared with other conditions. No difference was detectable for
end-apneic SaO2 or SaO2/t
between the control periods or the end of the study nights
(P > 0.6).
|
||||||||||||||||||||||||||||||||
DISCUSSION
In this study, consistent with previous work (6, 21), we found that apnea duration increased from C1 to C2. On the intervention night, compared with the same periods on the control night, topical UA anesthesia led to an increase in apnea duration at An1 but produced no change in apnea duration at An2.
Methodological issues. Before a discussion of the implications of these results, several methodological issues need to be addressed. The order of the control and anesthesia nights was randomized to reduce the risk that acclimatization to the laboratory could have resulted in spurious differences between the two nights. Because of the taste and rapid onset of action of the tetracaine, it was not possible for the subjects to be blinded to the intervention. However, there was no difference in sleep latency between the study and control nights, and none of the subjects complained afterward of adverse effects of the tetracaine. Furthermore, it seems unlikely that once sleep was established, knowledge by the patient of UA anesthesia would have influenced the measured parameters. The esophageal catheter could theoretically have decreased arousal time compared with a noncatheter study because of UA stimulation. As was found previously (15), however, mean apnea duration was similar between the original diagnostic and control nights. Therefore, it seems unlikely that the pleural pressure catheter had any independent effect on our results. To minimize the possibility that the lidocaine used to assist passage of the catheter influenced OSA, we required that >1 h elapse between catheter insertion and lights out. As well, the minimal amount of lidocaine necessary was used (<2 ml of a 4% viscous preparation). However, even in the unlikely event that the lidocaine used on control nights influenced the results, this would have had the effect of reducing the differences between control and anesthesia nights. We selected tetracaine (onset of action of 3-8 min and peak action of 30-60 min) because of concern that lidocaine would not provide a sufficiently long period of anesthesia during sleep. To avoid the confounding effects of declining efficacy, we restricted our analysis to within 1 h after lights out. Systemic absorption of drug was minimized by encouraging the subjects to expectorate rather than swallow excess saliva during anesthesia. Direct application of an anesthetic mixture containing 0.5% tetracaine to lacerations in children resulted in unmeasurable serum levels up to 1 h later (32), and doses of topical lidocaine comparable to that used in this study have not resulted in detectable side effects (1, 2, 7, 20). Hence we believe it is highly unlikely that the effects of topical airway anesthesia were due to central effects of tetracaine due to systemic absorption. Furthermore, administration of the same dose of tetracaine altered apnea duration at the beginning but not at the end of the night. Mechanisms of apnea termination in OSA. The termination of obstructive apnea is thought to require a brief arousal at or just before airway reopening (23, 26, 30). During apneas there is a progressive increase in inspiratory efforts, accompanied by progressive hypoxia and hypercapnia (30). Although arousal may be provoked by stimulation of peripheral (4) and/or central (3) chemoreceptors, recent work in animals and humans suggests that this may be mediated indirectly through an effect on ventilatory output, in that arousal appears to be most closely linked to the level of inspiratory effort (15, 21, 36). Recent evidence therefore points to a prominent role for effort-related mechanoreceptor stimuli generated during obstructed inspiratory efforts in mediating end-apneic arousal and apnea termination (15, 21). Study rationale and hypothesis. We have recently shown that apnea duration increases through the night in severe OSA (6, 21) and that this prolongation is associated with an increased level of inspiratory effort at end-apnea (21). We have argued that our findings were most consistent with an increase in the arousal threshold to effort-related stimuli through the night, thus leading to delayed end-apneic arousal and apnea prolongation (21). This could result from either a decrease over the course of the night in central arousal responsiveness to peripheral stimuli or to a progressive decline in peripheral-receptor sensitivity such that increased stimulus intensity is required to provide a level of afferent input sufficient to provoke arousal. The present study aimed to address the latter possibility. The peripheral receptors that may contribute to effort-mediated arousal have not been precisely identified, although evidence suggests that mechanoreceptors in the respiratory muscles and/or chest wall play a role (15, 21). In addition, UA mucosa has a rich sensory innervation, including mechanoreceptors responsive to fluctuations in transmural pressure (12, 13, 22, 28). Previous studies have indicated that such receptors may mediate feedback of inspiratory effort and the arousal response to airway occlusion (1, 13, 14, 19, 24, 28). For example, Issa et al. (14) compared time to arousal in response to face mask vs. tracheal occlusion in dogs and found that apnea duration was prolonged with tracheal occlusion. Basner et al. (1) reported that during induced face mask occlusion in normal subjects, topical UA anesthesia significantly increased the time to arousal and suction pressure at arousal from NREM sleep. As well, low-frequency vibration of the UA simulating snoring is a potent arousal stimulus in dogs (24). Thus UA mechanoreceptor stimuli may contribute to effort-related arousal in normal subjects. It seems probable that such a mechanism would also contribute to end-apneic arousal in OSA, in that intense stimulation of pressure-sensitive UA receptors would be expected during obstructed inspiratory efforts. This would result from both forceful suction collapse of the pharyngeal walls due to the highly negative intraluminal pressures (26) as well as caudal traction on pharyngeal structures due to transmission of negative intrathoracic pressure via the trachea and soft tissues of the neck. If UA sensory receptors do contribute to the arousal response to airway occlusion in OSA, are there data to suggest a possible mechanism by which impairment of this function could develop over the course of a night? UA events during sleep in subjects with OSA include vigorous snoring-related vibration (35) and repeated forceful suction collapse of the pharynx (26). These events could be traumatic to the UA mucosa and result in inflammation, edema, and possibly neural damage analogous to peripheral nerve injury resulting from low-frequency vibration (31). In support of this, UA mucosal edema has been demonstrated both in uvulopalatopharyngoplasty surgical specimens (35) and by using magnetic resonance imaging (27) in severe OSA patients. Of note, in the latter study, these changes reversed after treatment with nasal continuous positive airway pressure. Furthermore, palatopharyngeal muscle biopsies of OSA patients undergoing uvulopalatopharyngoplasty were also consistent with neurogenic damage (9). As well, Larsson et al. (16) demonstrated impaired oropharyngeal mucosal temperature sensation in OSA patients compared with age-matched nonsnoring controls, suggesting the development of a pharyngeal sensory neuropathy. Thus sensory abnormalities may be associated with the chronic effects of OSA. If this is indeed the basis of UA trauma during sleep (7, 17, 35), it seemed possible to us that sensory dysfunction, which may be chronically depressed compared with normal subjects, could worsen further over the course of a night due to the physical events in the UA during sleep. On the basis of the foregoing, we therefore hypothesized in the present study that 1) UA sensory receptors contribute to the arousal response to UA obstruction in OSA, particularly at the beginning of the night; and 2) there is an attenuation of UA sensory receptor function through the night, which necessitates an increase in inspiratory effort to produce arousal, thereby resulting in apnea prolongation. On the basis of these hypotheses, we predicted that UA mechanoreceptor blockade by using topical anesthesia would produce an increase in apnea duration at the beginning of the night compared with a time-matched control period but would produce little or no change in apnea duration at the end of the night. Interpretation of findings. We found that apnea duration and the number of apneic efforts increased from C1 to C2 by an amount comparable to those reported previously (6, 21). Consistent with our hypotheses, we found that apnea duration was increased at An1 compared with C1, this increase being comparable to that occurring spontaneously from C1 to C2. In contrast, UA anesthesia produced no further lengthening of apneas at the end of the night (Fig. 3). These findings are, therefore, consistent with a role for UA sensory receptors in mediating end-apneic arousal at the beginning of the night and with an attenuation of this function over the course of the night such that UA sensory inhibition by topical anesthesia no longer demonstrably affects apnea duration at the end of the night. Since we performed the studies reported here, two reports on the effects of UA anesthesia on apnea duration as well as other OSA-severity measures have appeared (2, 7). Berry et al. (2) assessed apnea duration and inspiratory effort at arousal during two consecutive 2-h periods on separate control and anesthesia nights. Nasooropharyngeal anesthesia with lidocaine was performed during the second 2-h period on the anesthesia night. Apnea length was unchanged in the second relative to the first 2 h of the control night but increased during UA anesthesia by a similar extent to that shown at the beginning of the night in the present study. The lack of apnea lengthening from periods 1 to 2 of the control nights was probably due to differences in timing and duration of the two periods compared with our study (and possibly related also to the insertion of extended nasal cannulas during the second 2-h period, which may have been disruptive to sleep and promoted earlier arousal). Overall, however, period 2 of these investigators appears to have been virtually identical to our C1 and An1 periods in terms of apnea duration and inspiratory effort at arousal on the control night and the effects of UA anesthesia on these variables. These findings, therefore, also support a role for UA sensory receptors in apnea termination. We speculate that the lack of an effect of UA anesthesia in our later period was not identified by these investigators due to the inclusion of data from earlier in the night in their period 2. In another recent study, Deegan et al. (7) assessed the effects on OSA of oropharyngeal anesthesia maintained through the entire night, compared with a control night. For the night overall, there was a nonsignificant tendency for apnea/hypopnea duration to increase with UA anesthesia. However, these workers did not assess changes in variables at successive time periods through the night. If the data from the beginning and end of the night in our study were pooled, it would have been difficult to detect lengthening of apnea duration with anesthesia. Hence the results of Deegan et al. are not directly comparable to our own but are not necessarily conflicting. These time-of-night considerations may also account for the apparent discrepancies between these two previous studies (2, 7) in terms of the effects of UA anesthesia in subjects with OSA. Although previous work is available that supports, or at least does not directly conflict with, our findings, this study is, therefore, unique in evaluating the effects of UA anesthesia on a time-of-night basis and in providing evidence of attenuated UA sensory function through the night. Further evidence for this needs to be established by direct testing of UA sensory function at the beginning and end of the night in OSA patients compared with normal subjects. An alternate explanation for an attenuated role for UA sensory receptors at the end of the night could be that central arousal responsiveness to peripheral stimuli declines at the end of the night, due either to specific habituation or to nonspecific circadian factors (6, 21). However, if responses to UA stimuli decrease on this basis, it would be expected that responses to other respiratory stimuli such as those arising in the chest wall/respiratory muscles should also be reduced. Thus even when UA receptors were inhibited on the anesthesia night, and these latter stimuli probably made a greater contribution to end-apneic arousal, apnea duration and inspiratory effort at arousal (measured as Pespeak) should still have increased through the night, which was not the case. Thus our findings provide indirect evidence against impaired central responsiveness to respiratory arousal stimuli as the mechanism for apnea's lengthening through the night. SaO2 data through the night. On the control nights, as in our previous studies (6, 21), end-apneic SaO2 showed no significant change from C1 to C2 (Table 4). In contrast, on the anesthesia nights, end-apneic SaO2 was significantly decreased at An1 compared with control but was no different at An2 from control and was therefore significantly higher than at An1. In that apnea duration was unchanged from An1 to An2, theSaO2/t
was greater at An1 than at An2 (Table 4). The reason for the difference
is unclear. There may have been a decline in
O2 consumption
(O2) through the night due to
circadian metabolic changes. We also assume that increased inspiratory
effort generation during apneas results in a higher O2. On control nights,
because of a trend to a greater
Pes/t at C2, the opposing
effects on SaO2 may have cancelled out.
In contrast, because Pes/t was
increased at An1
whenO2 was also likely to be higher, we speculate the combined effects led to a higher
rate of O2 and therefore
SaO2/t
(6, 21).
The consistency of end-apneic SaO2
through the control night raises the possibility of a primary role for
peripheral chemoreceptor stimuli in mediating end-apneic arousal (15,
21). Arguments have previously been provided against this possibility
(15, 21), and although these will not be reiterated here, the results of the present study further support this contention.
Specifically, if arousal were triggered by a critical level of
SaO2, at An1 apnea duration should have
decreased, not increased, due to the more rapid
SaO2/t.
By the same argument, apnea duration would have been expected to be
increased at A2 compared with An1 in view of the slower
SaO2/t,
which was not the case. A systemic central or peripheral chemoreceptor
effect of topical UA anesthesia cannot account for these findings in
that such an effect would have been expected to be observed at both
times of the night.
Inspiratory effort during apneas: influence of time of night and
anesthesia.
We had not initially anticipated the significantly greater
Pes/t during apneas and higher
Pespeak observed on the UA
anesthesia compared with control nights (Table 3). With respect to
Pes/t, the greater SaO2/t
observed at the beginning of the study nights (Table 4) may
have contributed to the increased
Pes/t during this period.
However, this mechanism cannot account for the comparable
Pes/t at An2, when
SaO2/t was considerably less. Another possibility is that UA sensory receptors play a role in the defense of
UA patency, in that UA anesthesia increases pharyngeal airflow resistance (8) and can induce or increase apneas and hypopneas in
normal subjects (20) and snorers (24). Although we observed no
systematic differences on the flow channel between the anesthesia and
control nights for the apneas analyzed, the oronasal thermistor (chosen
over other flow-measurement devices to minimize patient discomfort and
sleep disruption) (15) may not reliably detect low levels of airflow.
Thus we cannot discount the possibility that our UA anesthesia may have
increased UA collapsibility and led to "more complete" UA
obstruction during events and thereby a reflex increase in effort
during apneas.
The evidence that UA mechanoreceptors provide central feedback of
inspiratory effort has been discussed. The increased
Pes/t during apneas with UA
anesthesia would appear to indicate that UA mechanoreceptor feedback
has an inhibitory influence on inspiratory drive such that the marked
attenuation of UA sensation with tetracaine resulted in increased
inspiratory drive and effort. In support of this, afferent impulses
from other respiratory mechanoreceptors, e.g., in the chest wall and
respiratory muscles, may be inhibitory to inspiratory drive (29). Thus
sensory feedback from the UA may have also an inhibitory modulating
influence on ventilatory output, with the loss of this with UA
anesthesia thus leading to increased effort during apneas.
What might account for the greater
Pespeak on the anesthesia relative
to control nights? We propose that the increase in
Pespeak from the C1 to C2 is due
to a loss of afferent feedback from UA mechanoreceptors
due to attenuated receptor function through the night. This leads to a
requirement for greater activation (i.e., by a more intense effort) of
other respiratory afferents, such as those in chest wall and
respiratory muscles (15, 21), to produce a level of afferent stimulus
sufficient to provoke arousal and apnea termination. The extent of
inhibition of UA sensory receptors with topical UA anesthesia was
presumably greater than that which we propose occurred spontaneously
across the control night. Thus a greater level of effort again would be
required to activate other afferents to an extent sufficient to provoke arousal, accounting for the greater
Pespeak on anesthesia nights. The
lack of change in Pespeak from An1
to An2 (Table 3) is also consistent with these proposals, in that no
across-the-night attenuation of UA contribution as on control nights
would be anticipated in the face of similarly potent inhibition of UA
receptors at both times of the night with topical anesthesia.
One of the predictions from the data summarized above, indicating that
UA mucosal edema and sensory dysfunction may be present as chronic
effects of OSA (9, 17, 35), is that even at baseline, i.e., the
beginning of the night, UA sensation in OSA patients should be impaired
relative to normal subjects (and then become further attenuated over
the course of the night). Such a chronic defect, if present, could
account, in part, for the apparent impairment in arousal responsiveness
in OSA patients relative to normal subjects. That is, it has previously
been pointed out (15) that there is a marked difference between normal
subjects and OSA patients in time to arousal (15-20 vs. 25-30
s, respectively) and the level of inspiratory effort at arousal
(Pespeak 
15 to 17 cmH2O vs. 
50 cmH2O, respectively) in
response to airway occlusion during stage 2 sleep (15). These
differences are analogous to the effects of UA anesthesia at the
beginning of the night (C1 vs. An1, Table 3), which supports the
concept that impaired UA sensory function accounts for the reduced
arousal responsiveness in OSA patients relative to normal subjects.
However, this possibility needs to be documented by objective sensory
testing in both groups.
Finally, the interpretation of previous studies on effort-mediated
arousal has been problematic, in that it has not been possible to
definitively distinguish between afferent feedback related to a given
level of effort or the central drive responsible for producing that
effort as the primary stimulus for arousal. The results of the present
study demonstrate clearly that at the beginning of the night,
interruption of an afferent feedback mechanism, i.e., sensory stimuli
arising in the UA mucosa, leads to an impairment of the arousal
response and prolonged apnea duration. This therefore provides strong
support for the concept that effort-related afferent stimuli arising in
peripheral receptors play a determining role in the arousal response to
airway occlusion. The findings at the end of night are also in keeping
with this mechanism, in that if the level of drive were the determining
stimulus for arousal, apnea duration should have been shorter at the
end of the anesthesia compared with control nights, given the more
rapid increase in inspiratory drive and effort during apneas, which was
not the case.
In summary, our findings confirm previous observations that, in OSA,
apnea duration lengthens through the night and that apnea prolongation
is associated with an increased level of inspiratory effort at
end-apnea. The important new contribution of this study is that apnea
lengthening can also be produced by topical anesthesia-induced UA
mechanoreceptor blockade at the beginning of the night, whereas at the
end of the night the time-dependent increase and topical anesthesia-related increase in apnea duration are not different. We
believe these findings are most consistent with the conclusion that UA
mechanoreceptors provide important feedback of inspiratory effort
during apnea, but this function becomes less effective as the night
progresses so that arousal requires greater effort and is consequently
delayed. We speculate that attenuation of UA mechanoreceptor function
through the night in OSA is caused by repeated trauma to pharyngeal
tissues as a consequence of UA vibration and closure. The extent to
which changes in sleep events during the course of a single night may
resemble the increase in severity of UA obstruction over a longer
period is speculative. However, it is possible that further study of
these processes may serve as a useful model for, and provide new
insights into, the natural evolution of this disease.
ACKNOWLEDGEMENTS
The authors acknowledge the skillful assistance of the Royal Victoria Hospital Sleep Laboratory technical staff in performing the polysomnographic studies.
FOOTNOTES
Address for reprint requests: R. J. Kimoff, Rm. L4.08, Respiratory Div., Royal Victoria Hospital, 687 Pine Ave. W., Montreal, Quebec, Canada H3A 1A1 (E-mail: jkimoff{at}is.rvh.mcgill.ca).
Received 10 January 1996; accepted in final form 15 August 1996.
REFERENCES
| 1. | Basner, R. C., J. Ringler, E. Garpestad, R. M. Schwartzstein, D. Sparrow, S. E. Weinberger, J. Lilly, and J. W. Weiss. Upper airway anesthesia delays arousal from airway occlusion induced during human NREM sleep. J. Appl. Physiol. 73: 642-648, 1992. |
| 2. | Berry, R. B., K. G. Kouchi, J. L. Bower, and R. W. Light. Effect of upper airway anesthesia on obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 151: 1857-1861, 1995. |
| 3. | Berthon-Jones, M., and C. E. Sullivan. Ventilation and arousal responses to hypercapnia in normal sleeping humans. J. Appl. Physiol. 57: 59-67, 1984. |
| 4. | Bowes, G., E. R. Townsend, L. F. Kozar, S. M. Bromley, and E. A. Phillipson. Effect of carotid body denervation on arousal response to hypoxia in sleeping dogs. J. Appl. Physiol. 51: 40-45, 1981. |
| 5. | Chadwick, G. A., P. Crowley, M. X. Fitzgerald, R. G. O'Regan, and W. T. McNicholas. Obstructive sleep apnea following topical anesthesia in loud snorers. Am. Rev. Respir. Dis. 143: 810-813, 1991. |
| 6. | Charbonneau, M., J. M. Marin, A. Olha, R. J. Kimoff, R. D. Levy, and M. Cosio. Changes in obstructive sleep apnea characteristics through the night. Chest 106: 1695-1701, 1994. |
| 7. | Deegan, P. C., E. Mulloy, and W. T. McNicholas. Topical oropharyngeal anesthesia in patients with obstructive sleep apnea. Am. J. Respir. Crit. Care Med. 151: 1108-1112, 1995. |
| 8. | DeWeese, E. L., and T. Y. Sullivan. Effects of upper airway anesthesia on pharyngeal patency during sleep. J. Appl. Physiol. 64: 1346-1353, 1988. |
| 9. | Edstrom, L., H. Larsson, and L. Larsson. Neurogenic effects on the palatopharyngeal muscle in patients with obstructive sleep apnoea: a muscle biopsy study. J. Neurol. Neurosurg. Psychiatry 55: 916-920, 1992. |
| 10. | Gleeson, K., C. W. Zwillich, and D. P. White. The influence of increasing ventilatory effort on arousal from sleep. Am. Rev. Respir. Dis. 142: 295-300, 1990. |
| 11. | Horner, R. L., J. A. Innes, H. B. Holden, and A. Guz. Afferent pathway(s) for pharyngeal dilator reflex to negative pressure in man: a study using upper airway anaesthesia. J. Physiol. Lond. 436: 31-44, 1994. |
| 12. | Hwang, J., W. M. St. John, and D. Bartlett. Afferent pathways for hypoglossal and phrenic responses to changes in upper airway pressure. Respir. Physiol. 55: 341-354, 1984. |
| 13. | Hwang, J., W. M. St. John, and D. Bartlett. Receptors responding to changes in upper airway pressure. Respir. Physiol. 55: 355-366, 1984. |
| 14. | Issa, F. G., S. G. McNamara, and C. E. Sullivan. Arousal responses to airway occlusion in sleeping dogs: comparison of nasal and tracheal occlusions. J. Appl. Physiol. 62: 1832-1836, 1987. |
| 15. | Kimoff, R. J., T. H. Cheong, A. E. Olha, M. Charbonneau, R. D. Levy, M. G. Cosio, and S. B. Gottfried. Mechanisms of apnea termination in obstructive sleep apnea: role of chemoreceptor and mechanoreceptor stimuli. Am. J. Respir. Crit. Care Med. 149: 707-714, 1994. |
| 16. | Larsson, H., B. Carlsson-Nordlander, L. E. Lindblad, O. Norbeck, and E. Svanborg. Temperature thresholds in the oropharynx of patients with obstructive sleep apnea syndrome. Am. Rev. Respir. Dis. 146: 1246-1249, 1992. |
| 17. | Lundborg, G., L. Dahlin, H. A. Hansson, M. Kanje, and L. E. Necking. Vibration exposure and peripheral nerve fiber damage. J. Hand Surg. 15A: 346-351, 1990. |
| 18. | Mathew, O. P., Y. K. Abu-Osba, and B. T. Thach. Influence of upper airway pressure changes on genioglossus muscle respiratory activity. J. Appl. Physiol. 52: 438-444, 1982. |
| 19. | Mathew, O. P., G. Sant'Ambrogio, J. T. Fisher, and F. B. Sant'Ambrogio. Respiratory afferent activity in the superior laryngeal nerves. Respir. Physiol. 58: 41-50, 1984. |
| 20. | McNicholas, W. T., M. Coffey, T. McDonnell, R. O'Regan, and M. X. Fitzgerald. Upper airway obstruction during sleep in normal subjects after selective topical oropharyngeal anesthesia. Am. Rev. Respir. Dis. 135: 1316-1319, 1987. |
| 21. | Montserrat, J. M., E. N. Kosmas, M. G. Cosio, and R. J. Kimoff. Mechanism of apnea lengthening across the night in obstructive sleep apnea. Am. J. Respir. Crit. Care Med. In press. |
| 22. | Nail, B. S., G. M. Sterling, and J. G. Widdicombe. Epipharyngeal receptors responding to mechanical stimulation. J. Physiol. Lond. 204: 91-98, 1969. |
| 23. | Phillipson, E. A., and C. E. Sullivan. Arousal: the forgotten response to respiratory stimuli. Am. Rev. Respir. Dis. 118: 807-809, 1998. |
| 24. | Plowman, L., D. C. Lauff, M. Berthon-Jones, and C. E. Sullivan. Waking and genioglossus muscle responses to upper airway pressure oscillations in sleeping dogs. J. Appl. Physiol. 68: 2564-2573, 1990. |
| 25. | Rechtshaffen, A., and A. Kales (Editors). A Manual for Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Los Angeles, CA: UCLA Brain Information Service/ Brain Research Institute, 1968. |
| 26. | Remmers, J. E., W. J. deGroot, E. L. Sauerland, and A. M. Anch. Pathogenesis of upper airway occlusion during sleep. J. Appl. Physiol. 44: 931-938, 1978. |
| 27. | Ryan, C. F., A. A. Lowe, D. Li, and J. A. Fleetham. Magnetic resonance imaging of the upper airway in obstructive sleep apnea before and after chronic nasal continuous positive airway pressure therapy. Am. Rev. Respir. Dis. 144: 939-944, 1991. |
| 28. | Sant'Ambrogio, G., O. P. Mathew, J. T. Fisher, and F. B. Sant'Ambrogio. Laryngeal receptors responding to transmural pressure, airflow, and local muscle activity. Respir. Physiol. 54: 317-330, 1983. |
| 29. | Shannon, R. Reflexes from the respiratory muscles and costovertebral joints. In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986. sect. 3, vol. II, pt. 1, chapt. 13, p. 431-448. |
| 30. | Sullivan, C. E., and F. G. Issa. Pathophysiologic mechanisms in obstructive sleep apnea. Sleep 3: 235-246, 1980. |
| 31. | Takeuchi, T., M. Futatsuka, H. Imanishi, and S. Yamada. Pathological changes observed in the finger biopsy of patients with vibration-induced white finger. Scand. J. Work Environ. Health 12: 280-283, 1986. |
| 32. | Terndrup, T. E., H. C. Walls, P. J. Mariani, D. P. Gavula, C. M. Madden, and R. M. Cantor. Plasma cocaine and tetracaine levels following application of topical anesthesia in children. Ann. Emerg. Med. 21: 162-166, 1992. |
| 33. | Vincken, W., C. Guilleminault, L. Silvestri, M. Cosio, and A. Grassino. Inspiratory muscle activity as a trigger causing the airways to open in obstructive sleep apnea. Am. Rev. Respir. Dis. 135: 372-377, 1987. |
| 34. | White, D. P., J. V. Weil, and C. W. Zwillich. Metabolic rate and breathing during sleep. J. Appl. Physiol. 59: 384-391, 1985. |
| 35. | Woodson, B. T., J. C. Garancis, and R. J. Toohill. Histopathologic changes in snoring and obstructive sleep apnea syndrome. Laryngoscope 101: 1318-1322, 1991. |
| 36. | Yasuma, F., L. F. Kozar, R. J. Kimoff, T. D. Bradley, and E. A. Phillipson. Interaction of chemical and mechanical respiratory stimuli in the arousal response to hypoxia in sleeping dogs. Am. Rev. Respir. Dis. 143: 1274-1277, 1991. |
This article has been cited by other articles:
|
|
 |
|
  J. H. Mateika and G. Narwani Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol, March 1, 2009; 94(3): 279 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Schwartz, S. P. Patil, H. Schneider, and P. L. Smith Modelling pathogenic mechanisms of upper airway dysfunction in the molecular age Eur. Respir. J., August 1, 2008; 32(2): 255 - 258. [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Beecroft, V. Hoffstein, A. Pierratos, C. T. Chan, P. McFarlane, and P. J. Hanly Nocturnal haemodialysis increases pharyngeal size in patients with sleep apnoea and end-stage renal disease Nephrol. Dial. Transplant., February 1, 2008; 23(2): 673 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Beecroft, V. Hoffstein, A. Pierratos, C. T. Chan, P. A. McFarlane, and P. J. Hanly Pharyngeal narrowing in end-stage renal disease: implications for obstructive sleep apnoea Eur. Respir. J., November 1, 2007; 30(5): 965 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ahuja, J. H. Mateika, M. P. Diamond, and M. Safwan Badr Ventilatory sensitivity to carbon dioxide before and after episodic hypoxia in women treated with testosterone J Appl Physiol, May 1, 2007; 102(5): 1832 - 1838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Jobin, V. Champagne, J. Beauregard, I. Charbonneau, D. H. McFarland, and R. J. Kimoff Swallowing function and upper airway sensation in obstructive sleep apnea J Appl Physiol, April 1, 2007; 102(4): 1587 - 1594. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Doherty, P. Nolan, and W. T. McNicholas Effects of topical anesthesia on upper airway resistance during wake-sleep transitions J Appl Physiol, August 1, 2005; 99(2): 549 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Boyd, B. J. Petrof, Q. Hamid, R. Fraser, and R. J. Kimoff Upper Airway Muscle Inflammation and Denervation Changes in Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., September 1, 2004; 170(5): 541 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gozal and M. M. Burnside Increased Upper Airway Collapsibility in Children with Obstructive Sleep Apnea during Wakefulness Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 163 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bottini, M.L. Dottorini, M. Cristina Cordoni, G. Casucci, and C. Tantucci Sleep-disordered breathing in nonobese diabetic subjects with autonomic neuropathy Eur. Respir. J., October 1, 2003; 22(4): 654 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Oksenberg, I. Khamaysi, and D.S. Silverberg Apnoea characteristics across the night in severe obstructive sleep apnoea: influence of body posture Eur. Respir. J., August 1, 2001; 18(2): 340 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. JOHN KIMOFF, E. SFORZA, V. CHAMPAGNE, L. OFIARA, and D. GENDRON Upper Airway Sensation in Snoring and Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 250 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tun, W. Hida, S. Okabe, Y. Kikuchi, H. Kurosawa, M. Tabata, and K. Shirato Inspiratory Effort Sensation to Added Resistive Loading in Patients With Obstructive Sleep Apnea Chest, November 1, 2000; 118(5): 1332 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. KIMOFF, D. BROOKS, R. L. HORNER, L. F. KOZAR, C. L. RENDER-TEIXEIRA, V. CHAMPAGNE, P. MAYER, and E. A. PHILLIPSON Ventilatory and Arousal Responses to Hypoxia and Hypercapnia in a Canine Model of Obstructive Sleep Apnea Am. J. Respir. Crit. Care Med., September 1, 1997; 156(3): 886 - 894. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
