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Published ahead of print on December 18, 2003, doi:10.1164/rccm.200307-1023OC
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American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 623-633, (2004)
© 2004 American Thoracic Society

Role of Arousals in the Pathogenesis of Obstructive Sleep Apnea

Magdy Younes

Department of Medicine, University of Manitoba, Winnipeg, Manitoba; and Department of Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Magdy Younes, M.D., Ph.D., 3611-55 Harbour Square, Toronto, ON, Canada M5J 2L1. E-mail: mkyounes{at}sympatico.ca


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Arousal is believed to be needed for upper airway opening in obstructive hypopneas–apneas, without compelling evidence to support this notion. The association may be incidental. I studied the temporal relation between arousal and opening and impact of arousal on flow response at opening in 82 patients (apnea–hypopnea index, 46 ± 35/hour). Obstructive apneas–hypopneas were induced by dial-down of continuous positive airway pressure. Obstructions and hypopneas occurred in 44 and 56% of dial-downs, respectively. When arousal occurred (83% of dial-downs), the temporal relation between arousal and opening was inconsistent between and within patients. Frequency of opening without or before arousal increased with milder obstructions (p < 10-9) and with delta power of EEG (p < 10-6). Time of opening was unaffected by whether arousal occurred before or after opening (18.0 ± 9.8 vs. 18.1 ± 10.5 seconds). Flow response was already excessive when opening occurred without or before arousal (180 ± 148% of initial flow decline) and was considerably higher when arousal occurred (267 ± 154%, p < 10-10). Flow undershoot after first ventilatory response was greater if arousal occurred (p < 0.01). It is concluded that arousals are incidental events that occur when thresholds for arousal and for arousal-independent opening are close. They are not needed to initiate opening or to obtain adequate flow and they likely increase the severity of the disorder by promoting greater ventilatory instability.

Key Words: obstructive sleep apnea • mechanisms • ventilatory stability

Arousal from sleep is believed to be an important, if not essential, mechanism for reestablishing airway patency in obstructive sleep apnea (OSA). Originally proposed by Remmers and coworkers (1), this notion was bolstered over the years by the everyday observation that obstructive apneas and hypopneas end abruptly and almost invariably with arousal. The suddenness of increase in flow suggests a discontinuous mechanism, unlike chemical and mechanoreceptor feedback. The concurrent arousal provides a perfect explanation for this discontinuous behavior. This notion is currently so strong that when arousals are not seen at event termination it is presumed that they exist but we failed to detect them.

The preeminence of arousal is based on temporal association between arousal and upper airway (UA) opening. The association may be incidental or even causal in an opposite sense; arousals causing OSA. An incidental association may occur if thresholds for arousal and arousal-independent UA opening are similar. An opposite causal association may result if arousals occur too soon, preempting an orderly compensation by reflex mechanisms. In this case, recurrent cycling (OSA) would occur when arousal threshold is low and would disappear when threshold rises. These alternate possibilities are not without support. (1) Some obstructive events terminate without obvious cortical arousal (2–8). These have generally been attributed to insensitive arousal identification criteria, occurrence of arousal in unmonitored cortical areas, or to unconventional presentation of arousal (delta, subcortical, autonomic, etc.) (see Berry and Gleeson [4] for review). Perhaps these arousal-free events represent one end of a loose incidental association. (2) Patients frequently alternate between recurrent OSA and stable breathing under conditions where such changes cannot be explained by differences in UA collapsibility (9). (3) Stable breathing tends to occur in delta sleep, when arousal threshold is high (10–12). (4) Progressive recruitment of UA dilators before arousal (i.e., without arousal) is well documented in patients with OSA (1, 3, 13–16) and level of activity may exceed waking levels (3). (5) Arousal is triggered when a critical level of chemo/mechanoreceptor input is reached (4, 17–22). Arousal-independent recruitment of UA dilators is sensitive to the same inputs (16, 23–29). Clearly, situations may occur when the input required for triggering arousal and for activating UA muscles enough to open the airway is similar.

In this study, rapid dial-downs of continuous positive airway pressure (CPAP) from a stable baseline were used to induce obstructive apneas–hypopneas in patients with OSA. The role of arousals was examined by: (1) documenting the temporal relation between UA opening and arousal. If arousal is required for UA opening, there should be a predictable relation between the two events under different conditions. Conversely, if the relation is incidental, this relation should be variable. (2) Comparing the magnitude of increase in flow with and without arousal at UA opening. This would establish whether arousals play a helpful or harmful role. A helpful role may be surmised if flow response without arousal is inadequate. Conversely, an adequate or excessive response without arousal that is further augmented by arousal would suggest a harmful role because an excessive ventilatory response helps perpetuate cycling (30–33). (3) Determining whether severity of the next hypopnea is greater if arousal occurred at end of the first hypopnea–apnea. The advantages of dial-downs from CPAP over observations on spontaneous obstructive events are outlined in the online supplement.

This is the second report from this study. Earlier (9), I described the effect of passive abnormalities, as reflected by the lowest flow during dial-downs, on severity of OSA. A preliminary report of the current findings was published (34).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A more detailed account of METHODS is given in the online supplement.

Patients, protocol, and general methods are identical to those reported earlier (9). Briefly, 82 patients referred for possible OSA were studied using standard polysomnography. CPAP was titrated after obtaining enough information for clinical evaluation. Flow, airway pressure, and polysomnography signals were recorded. Pressure was dialed-down to 1 cm H2O during stable sleep. Dial-down was maintained until arousal or 60 seconds. In approximately one third of interventions, dial-downs were maintained for 2–3 minutes to document the response beyond the first ventilatory phase.

Analysis

  • Polysomnography before dial-downs: sleep, arousals, and respiratory events were scored using standard criteria (35–37). Time spent with stable breathing was defined as sleep periods without respiratory events in excess of 3 minutes (9).
  • Dial-downs. Flow signal was offset by the leak. Mean inspiratory flow (VT/TI) and tidal volume (VT) during baseline (60 seconds preceding dial-down) were calculated. Flow and VT were measured breath by breath after dial-down. Onset of flow response (Tflow) was identified from the point at which there was a clear increase in flow (Figures 1 and 2) . The lowest flow observed before Tflow was noted (min). min reflects passive collapsibility (9). Dial-downs were classified according to the relation between Tflow and Tarousal:



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  		Figure 1. Tracings of EEG (C3/A2), heart rate, flow, and airway pressure illustrating some of the measurements. Baseline VT/TI, mean inspiratory flow on continuous positive airway pressure (CPAP). A = arousal; Tflow = time at which a flow response began; Br1 and Br2 = peak flow in the first and second breaths of the flow response; min = lowest flow reached before Tflow in the first hypopnea; min2 = lowest flow after the first ventilatory phase.
 


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  		Figure 2. Tracings of EEG (C3/A2 and O2/A1), flow, chin EMG, and heart rate showing examples of the three response types. Two open arrows in A and C indicate onset of CPAP dial-down and time at which pressure reached 1.0 cm H2O, respectively. In B, dial-down occurred before the illustrated section. A short baseline segment is shown to the left. Solid upward pointing arrows indicate UA opening. Solid downward pointing arrows indicate onset of arousal (B and C). (A) Type 1 response. Note upper airway (UA) opening without arousal. (B) Type 2 response. Arousal begins 0.7 second after UA opening. Note the appearance of crescendo phasic inspiratory chin EMG activity (asterisks) late in the apnea. The third such phasic burst is associated with UA opening and a loud snort. The declining phase of the third burst merges with tonic activation associated with arousal. (C) Type 3 response. UA opening occurs 0.6 second after arousal.
 
Type 1 (Figure 2A): no arousal.
  • Type 2 (Figure 2B): Tflow occurred first but an arousal occurred later between 0.3 and 15.0 seconds.
  • Type 3 (Figure 2C): an arousal occurred before, or within 0.3 seconds after, Tflow.

Definition of Arousals and their Onset (Tarousal)
A more detailed account of DEFINITION OF AROUSALS AND THEIR ONSET (TAROUSAL) is given in the online supplement.

A combination of EEG inspection and Fourier analysis was used. First, three EEG leads were inspected for a high-frequency shift greater than 3 seconds. If so, Tarousal was the earliest point where the change occurred in any lead. A central EEG lead was analyzed by discrete Fourier transform in 3-second, nonoverlapping epochs spanning baseline (20 epochs) and dial-down. EEG power in the delta, theta, alpha, sigma, and beta ranges was computed. Confidence interval of 95% in baseline epochs was calculated for each frequency band. An arousal was deemed present at Tflow if a visible arousal that meets conventional criteria (36) was present or if total high-frequency power (7.3–35.0 Hz) in the Tflow epoch was greater than the upper bound of the 95% confidence interval.

In several cases, total high-frequency power at Tflow was within baseline range but there was a significant increase in one or more frequency ranges. Classification of dial-down as type 1 to 3 was not altered. However, to assess the impact of such isolated frequency changes, analysis of type 1 and 2 responses was done with and without inclusion of these dial-downs.

Additional Measurements
Latencies to Tflow and Tarousal: interval between onset of dial-down and Tflow and Tarousal.

  • Heart rate at Tflow: heart rate was measured from the beat straddling Tflow and at the corresponding time in inspiration (to account for sinus arrhythmia) in the two preceding breaths.
  • Arousal intensity at Tflow was rated by a single observer, on a scale of 0 to 4 (0 = no arousal), using a subjective scale (see Figure E2 in the online supplement).
  • Flow response at Tflow ({Delta}1) was calculated from [Br1 - min] (Figure 1). ({Delta}1) was expressed in liters per second and as the ratio of initial reduction in flow [flow response ratio = (({Delta}1/(baseline VT/TI - min))). This ratio reflects effectiveness of Breath 1 response in restoring flow to normal. The impact of arousal intensity on flow response was assessed by analysis of variance. Similar calculations were done for the next breath ({Delta}Br2) in type 1 and type 2 observations.
  • The tendency for self-perpetuation was assessed as follows (Figure 1). The lowest flow beyond the first ventilatory response in long dial-downs was measured (min2). Severity of the second hypopnea (baseline VT/TI - min2) was expressed as a fraction of severity of first hypopnea (baseline VT/TI - min) (severity ratio). Ratios of 0 and 1.0 indicate, respectively, no tendency and maximum tendency for self-perpetuation.

Results are expressed primarily as those of individual dial-downs. Where appropriate, average of results in all dial-downs in individual patients was computed (e.g., average response type, average flow response ratio, etc.). All values are mean ± SD except where indicated.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients were predominantly middle-aged, obese men (Table 1) . Overall apnea–hypopnea index was 46.0 ± 35.0/hour. Although apnea–hypopnea index varied widely (2–146, Table 1), the type of respiratory disturbance was obstructive in all patients. Other polysomnographic findings are shown in Table 1 (see online supplement for a more detailed account of RESULTS).


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  		TABLE 1. Patient demographics and results of polysomnography

 
A total of 525 dial-downs were examined. Of these, 138 (26%) were in REM sleep. min percentage varied considerably (Table 2) . On average, it was 20.2 ± 25.2%. Latency to Tflow was 18.1 ± 10.6 seconds, and latency to Tarousal in type 2 and 3 observations was 17.7 ± 11.0 seconds.


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  		TABLE 2. Some characteristics of dial-downs (n = 525)

 
Frequency of Different Response Types
The frequency of types 1, 2, and 3 was 17, 22, and 61%, respectively (Table 2). Figure 2 shows examples of the three response types. Additional examples are shown in Figures E3–E5 in the online supplement. Figure 3 shows the frequency distribution according to time difference ({Delta}T) between Tflow and Tarousal. There was a peak (32%) at zero (±0.3 seconds). In a substantial percentage of dial-downs (29%) arousal did not trigger an increase in flow immediately (Figure 3, e.g., Figure 2C and Figure E5 in the online supplement).



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  		Figure 3. Frequency of observations having different intervals between UA opening and arousal ({Delta}T).

 
The relation between Tflow and Tarousal was inconsistent in individual patients. A total of 64 patients (78%) had different types at different times (see Figure E6 in the online supplement). Only 18 patients (22%) had exclusively type 3 responses. These patients were not different from the other 64 patients regarding age, sex, body mass index, or apnea–hypopnea index. However, they had a more collapsible airway (min%: 7.6 ± 17.9 vs. 27.4 ± 29.4, p < 0.005).

Determinants of Response Type
Figure 4A shows the probability of different response types as a function of severity of obstruction (min). With complete obstruction in NREM, very few type 1 responses were seen (8%). As hypopnea severity decreased, the proportion of type 3 decreased and that of type 1 increased (p < 10-9, {chi}2 test).



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  		Figure 4. (A) Probability of different response types as a function of obstructive severity min. (B) Probability of different response types as a function of delta power. Delta power of 13, 20, 22, and 26 dB correspond to Stage 1, Average Stage 2, Deep Stage 2, and Stage 4 NREM sleep, respectively. Solid symbols, NREM sleep; open symbols, REM sleep.

 
Figure 4B shows the impact of delta power at baseline on the proportion of different types. At the lowest delta power in NREM (13 dB, comparable to Stage 1) there were few type 1 responses. The proportion of type 3 responses decreased, whereas that of type 1 increased as delta power increased (p < 10-6, {chi} test). At 26 dB (deep Stage 4), the frequencies of types 1 and 3 were comparable. The effect of delta power was continuous throughout the range of NREM sleep, with most of the change occurring in the range of Stage 2 (~ 16–22 dB). There was no correlation between delta power and min% (r = 0.015), indicating that the observed changes were not due to differences in mechanical severity.

At the same min, there were significantly more type 3 responses and less type 1 responses in REM than in NREM sleep (p < 0.001; open symbols, Figure 4A). With complete obstruction, virtually no type 1 responses were seen. However, there was no difference in type distribution between REM and NREM when the data were plotted as a function of delta power (open symbols, Figure 4B).

Stepwise regression was performed to identify factors that correlate with probability of different types. Delta power, min, and body mass index had significant independent effects (p < 10-12, p < 10-21, and p < 0.002, respectively). REM sleep had no effect after allowing for delta power and min. Age, sex, body position, clock time, and baseline values of heart rate, E, and O2 saturation also had no effect. The regression equation (r = 0.49, p < 10-30) was:

An almost identical regression was obtained when the average values of response type, min%, and delta power obtained in each patient were used (p < 10-7):

Thus, a nonobese patient in REM or Stage 1 sleep (delta = 14 dB) who develops a complete obstruction (min = 0) would have a response type of 3.0 (all events are type 3). In contrast, an obese patient (body mass index = 40), in deep Stage 2 or delta sleep (delta = 23 dB) who develops a mild hypopnea (e.g., min = 70%) would have a response type of 1.5 (i.e., 50% type 1, 50% type 2 and no type 3, or 75% type 1, 25% type 3, etc.).

Impact of Arousal on Tflow
For all data, latency to Tflow was not different among types (17.7 ± 9.7, 18.6 ± 11.1, and 18.0 ± 10.6 second, p = 0.82 by analysis of variance). In contrast, latency to arousal was longer in type 2 than in type 3 (21.6 ± 11.7 vs. 16.4 ± 10.3 second, p < 10-5). These findings suggest that UA opening would occur at the same time, regardless of when arousal occurs.

This potentially important finding was tested further such that each patient was his/her own control. Patients who had type 3 responses and either type 1 or type 2 responses were identified. The difference between average latency to Tflow in either type 1 or type 2 and latency to Tflow in type 3 observations was computed in each patient. The same was done for latency to Tarousal in types 2 and 3. In type 2, Tarousal occurred 5.7 ± 7.7 seconds later than in type 3 (p < 10-5, n = 45 patients, Figure 5) , whereas Tflow was not different (0.4 ± 7.1 second, p = 0.4). min was comparable. Tflow was marginally delayed in type 1 relative to type 3 observations (2.8 ± 11.3 seconds, p = 0.07, n = 35 patients). However, min was, on average, higher by 19 ± 12.4% (p < 10-5), indicating milder hypopneas. Multiple regression with Tflow as the dependent variable versus type, delta power and min revealed no effect of type (p = 0.9) or, importantly, of delta power (p = 0.17) on Tflow. The effect of min was significant (p < 0.0002, coefficient = 0.15 seconds/% baseline flow). Thus, opening occurred at the same time regardless of delta power or whether or when arousal occurred.



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  		Figure 5. Latency to upper airway opening (Tflow) and to arousal in observations with different response types. All values were referred to latency in type 3 responses in the same patient. Bars represent 1 SEM. *Significantly different from type 3 (p < 10-5). Latency to Tflow was the same whether arousal occurred before (type 3) or after (type 2) UA opening. Latency to Tflow was slightly longer in type 1 responses but this is due to the milder nature of obstructive events in this response type (see text).

 
Impact of Arousal on Magnitude of Flow Response
First breath (see online supplement). Figure 6 shows the effect of arousal intensity at Tflow on flow response in the first breath showing a response. The response is given in absolute units (L/second) or as the ratio of initial flow decline (right axis). A ratio greater than 1.0 indicates overcompensation. Without arousal (types 1 and 2), flow increased 0.30 ± 0.24 L/second, corresponding to a ratio of 1.80 ± 1.48 (p < 10-11 for difference from 1.0). There was a progressive increase in flow response and flow response ratio as arousal intensity increased (p < 10-25 and p < 10-13, respectively, by analysis of variance). Response ratio approached four with the most intense arousals.



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  		Figure 6. Effect of arousal intensity on flow response at UA opening (first breath). Response is expressed either in flow units (left axis) or as a ratio of the initial decline in flow. Data at intensity of zero are the average of the points in type 1 and 2 observations (no arousal). Bars represent 1 SEM.

 
Second breath in types 1 and 2 (see online supplement). Flow response in Breath 2 varied depending on magnitude of first breath response and whether an arousal developed by Breath 2 (Figure 7) . When there was still no arousal, flow generally increased when Breath 1 response was incomplete (flow response ratio = 0.94 ± 0.55 vs. 0.67 ± 0.22, p < 0.001, Figure 7, lower dashed line) and did not change when Breath 1 response was excessive (Figure 7, upper dashed line). In contrast, when arousal developed by Breath 2, flow was higher regardless of whether Breath 1 response was incomplete or excessive (solid lines, Figure 7). Flow response ratio of Breath 1 was no different whether an arousal was imminent (Figure 7, solid symbols) or not.



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  		Figure 7. Changes in flow response from first to second breath after UA opening in types 1 and 2 (i.e., no arousal in Breath 1). Open symbols: no arousal in second breath. Closed symbols: arousal occurred between first and second breaths. Observations are segregated into those in which first breath response was inadequate (i.e., < 1.0, lower set) and those with excessive response. Bars represent 1 SEM. *Significantly different from Breath 1 response (p < 0.001). + significantly different from second breath without arousal (p < 0.001). Breath 1 responses were not different whether arousal was imminent (closed symbols) or not.

 
Impact of Arousal on Response Beyond the First Ventilatory Phase
Figure 8 shows the spectrum of responses in long dial-downs (n = 182). In the top tracing, min2 was not lower than baseline mean inspiratory flow (severity ratio = 0). In the middle tracing, a second hypopnea developed, but it was less severe than the first (severity ratio 0.5). In the bottom tracing, the second hypopnea was as severe. The entire spectrum of ratios (0–1.0) was seen with and without an intervening arousal, but the average ratio was greater after an arousal (0.76 ± 0.38 vs. 0.60 ± 0.39; p < 0.01). Severity ratio correlated with intensity of arousal (r = 0.25, p < 0.001). With Level 4 arousal, severity ratio was 0.93 ± 0.19.



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  		Figure 8. Three examples illustrating range of responses following first ventilatory phase. A = arousal; Paw = airway pressure. Top: minimum flow after first ventilatory phase (min2) similar to average baseline flow on CPAP. Middle: a second hypopnea develops but it is milder than the first. Bottom: second hypopnea as severe as first.

 
Heart Rate at Tflow in Types 1 and 2
Rather than being higher, heart rate at Tflow in types 1 and 2 (63.2 ± 9.0/minute) was lower than in the preceding two breaths (63.9 ± 10.1 in the immediately preceding breath and 64.3 ± 10.7/minute two breaths back; p < 0.05 by analysis of variance for repeated measures).

EEG and EMG Changes at Tflow in Types 1 and 2
(See online supplement for a more detailed account of EEG AND EMG CHANGES AT TFLOW in Types 1 and 2)

In 30% of type 1 and 2 observations (i.e., no high-frequency arousal), delta power was significantly higher at Tflow than at baseline. In an additional 15% there were significant increases in one or more higher frequency bands but not enough to increase total high-frequency power (see Table E1 in the online supplement). The impact of these changes was assessed by comparing flow response ratio and heart rate in observations with (45%) and without such changes. Flow response ratio was not different (1.88 ± 1.59 vs. 1.73 ± 1.39; p = 0.45, see also Figure E7A in the online supplement). Heart rate was lower at Tflow than in the preceding two breaths in both cases, and the magnitude of reduction was similar (see Figure E9 in the online supplement).

Changes in EMG were infrequent in type 1 and 2 observations (see online supplement).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main findings are: (1) While arousal and UA opening occur, on average, at the same time, the temporal relation between the two events is inconsistent within and between patients. (2) UA opening occurs at the same time regardless of whether arousal occurs before or after UA opening or does not occur at all. (3) The increase in flow at UA opening is already excessive in the absence of arousal. Thus, arousal is not required for an adequate flow response. (4) The effect of arousal on UA function is not manifest until there is a clear high-frequency change in EEG. (5) The occurrence of cortical arousal at UA opening is associated with a greater flow overshoot and a greater subsequent undershoot.

Were Arousals Really Absent at Tflow in Types 1 and 2?
Several previous reports noted the occurrence of UA opening without overt arousal (2–8). A number of explanations were proposed that would still be consistent with arousal-mediated opening (see Berry and coworkers [4] for review). What follows is a discussion of these possibilities and how they were addressed in this study.

  1. An increase in EEG high frequency may be present but is equivocal or it lasts less than 3 seconds. This was addressed by comparing EEG power spectrum at UA opening with 20 baseline epochs. Arousal was called when high-frequency content was significantly higher than baseline even if the change did not meet conventional criteria. This analysis would detect arousals even if the increase in high frequency involved a fraction of the epoch, so long as the change is outside the range observed in baseline.
  2. Arousal may take the form of an increase in slow wave activity. Some investigators noted an increase in delta power near the end of obstructive events (8, 38). The significance of this phenomenon is unknown. Some believe it is an early or mild form of arousal (see Sforza and coworkers [39] for a review). Others believe it represents accelerated progression to deep sleep in sleep-deprived patients (38). An increase in delta was found in 30% of observations classified as type 1 or 2 (see Table E1 in the online supplement). There was, however, no difference in flow response whether such changes were present or not (see Figure E7A in the online supplement). Thus, even if delta increases are considered as arousals, they cannot be responsible for UA opening.
  3. Arousals may be present without any cortical changes (subcortical or autonomic arousals). This possibility was excluded by demonstrating that heart rate was not higher at UA opening (in fact it was lower) than in the preceding breaths. The evidence for subcortical arousals stems from observations that external stimuli (e.g., acoustic) can increase heart rate and blood pressure even without cortical arousals (40, 41). Although heart rate and blood pressure responses to external stimuli may vary in individual subjects, the average responses invariably involve an increase in both variables (41–44). Thus, lack of an average increase in heart rate at UA opening in types 1 and 2 effectively rules out autonomic arousals at UA opening (an increase in blood pressure may still occur at UA opening, however, because of the increase in intrathoracic pressure [decreased cardiac afterload] and reduction in pulmonary vascular resistance as a result of improvement in alveolar gas tensions). Because respiratory muscle responses with subcortical arousals are considerably less than the autonomic response (compare ventilatory response to subcortical arousal in Badr and coworkers [45] with autonomic response in the same subjects in Morgan and coworkers [41]), lack of an autonomic response makes it extremely unlikely that UA opening in these cases was produced by subcortical arousals. Two observations from this study further support this conclusion:
  4. First, flow response in Breath 1 was similar whether cortical arousal was imminent (arousal in Breath 2) or not (Figure 7). To the extent that activity in subcortical mechanisms must have been higher when arousal was imminent, this lack of difference suggests that subcortical arousal mechanisms do not exert an important effect on UA dilators.
  5. Second, flow response in types 1 and 2 was, on average, 52% of the response in type 3 (data from Figure 6). It is difficult to explain this magnitude by arousals that could not be seen, could not be detected by Fourier analysis, and that were not strong enough to mount a pressor response. Basner and coworkers (46) found that acoustic stimuli applied during spontaneous obstructive apneas decreased their duration by 2 seconds when no overt (> 3 seconds) cortical arousal resulted. This was only 20% of the reduction produced by stimuli with overt arousal. This value of 2 seconds overestimates the potency of subcortical arousals; in most cases classified as "no arousal," there were cortical changes that did not meet standard criteria (see discussion in Basner and coworkers [46]). Thus, the potency, if any, of subcortical mechanisms in opening UA is miniscule.
  6. Cortical arousals may be present in unmonitored areas. See online supplement.
  7. In a minority of type 1 and 2 observations, there were changes in one or more high-frequency bands, but they were not sufficient to increase total high-frequency power above baseline (see Table E1 in online supplement). These are almost certainly analytical or technical artifacts (see online supplement). Furthermore, neither flow response (see Figure E7A in the online supplement) nor heart rate response (see Figure E9 in the online supplement) was different in these cases from responses where there were no EEG changes at all.

Frequency of Different Response Types
(A more detailed account of FREQUENCY OF DIFFERENT RESPONSE TYPES is given in the online supplement.)

The frequency of type 1 response (17%, Figure 3) is well within previously reported incidence of obstructive events ending without arousal (2, 3, 5, 7, 8). Dingli and coworkers (7) noted that spontaneous obstructive events occurring in delta sleep are less frequently associated with visible arousals. Current results extend this finding by showing that frequency of type 1 response increases continuously with delta power, with most of the change occurring in the delta range of Stage 2 sleep (16–22 dB, Figure 4B). Thus, in some patients, a small change in delta power within Stage 2 may cause arousals to disappear.

There are no formal reports of frequency of type 2 responses, although the occurrence of arousal after UA opening is a common finding in sleep records and is evident in some published records (e.g., figures 1 and 2 in Stradling and coworkers [47]). Frequency of type 2 responses showed no consistent relation with delta power or obstructive severity (Figure 4), suggesting that this type is transitory. As delta power increases, or obstructive severity decreases, some type 3 responses become type 2, whereas some type 2 responses become type 1, leaving frequency of type 2 responses unchanged.

Evidence for Nonessentiality of Arousal
This study produced much evidence that arousal is not essential for UA opening:

  1. The relation between Tflow and Tarousal was quite inconsistent (Figure 3). If arousal causes opening, why does it occur sometimes before and sometimes after opening, even in the same patient? Most patients (78%) displayed different types at different times and, even within the same response type in the same patient, the difference between Tflow and Tarousal varied considerably (see Figure E6 in the online supplement). This strongly suggests that the association is incidental.
  2. Type 3 was much less frequent when obstruction was milder (Figure 4A). If arousal is required for UA opening with a severe hypopnea, why is it not required with a milder one? That UA opening can occur without arousal at any obstruction severity indicates that the relation between UA dilators' activation and opposing forces is such that the dilators prevail, in due course, without arousal. If so, it is difficult to envision a scenario whereby UA dilators can prevail without arousal at one level of severity but not at a higher one (Figure 9) .
  3. Frequency of UA opening without arousal increased with delta power (Figure 4B). Why should arousal be needed in light but not deep sleep? Obstruction was no less severe. Latency to UA opening was also not affected by delta power. Thus, dynamics of compensatory responses were not different. Arousal threshold increases with delta power (10–12). The most reasonable interpretation is that arousal-independent compensatory mechanisms are capable of opening the UA, but when arousal threshold is low, arousal occurs first or concurrently.
  4. Dingli and coworkers (7) and Rees and coworkers (2) reported that duration of spontaneously occurring apneas–hypopneas was not different whether or not an arousal occurred (i.e., type 1 vs. types 2 and 3). Perhaps, it may be argued, that in a minority of events (i.e., type 1) arousal-free compensation is possible but in the majority (types 2 and 3) arousal is needed. However, in this study latency to opening was the same whether arousal occurred before (type 3) or after (type 2) opening (Figure 5). What was different was latency to arousal (Figure 5). The inescapable conclusion is that arousal is irrelevant to when UA opening occurs.



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  		Figure 9. Models of UA opening to show that if UA can open without arousal at one level of obstructive severity, it should be able to do the same with more severe obstructions. Large solid arrows: actual relation between negative pharyngeal pressure and dilator activity. Dashed lines: relation required for UA opening (i.e., flow to appear in complete obstructions or to increase in hypopneas). (A) The familiar "balance of forces" model (1). Dilator activity increases progressively during the obstructive event, but so does the opposing negative pharyngeal pressure. If the two lines are diverging or parallel, UA opening cannot occur unless an extraordinary event, such as arousal, increases dilator activity relative to opposing pharyngeal pressure such that the relation moves to the right of the dashed line. (B) and (C) Two possible explanations for UA opening without arousal using the "balance of forces" model. In (B), the actual relation is nonlinear such that crossing to the right of the dashed line occurs spontaneously. In (C) the two lines are converging. In either case, if crossing can occur spontaneously at one level of obstructive severity, it should do so with a more severe obstruction because the pharyngeal pressure at which spontaneous crossing occurs is reached more readily. (D) Another model of UA opening in which the dilator activity required to open airway is a function of obstructive severity and independent of pharyngeal pressure (on the grounds that downstream pharyngeal pressure is not transmitted to the site of occlusion or flow limitation). H1, mild hypopnea; H2, severe hypopnea; O1 and O2 are two occlusions with different opening pressures. Spontaneous UA opening at H1 signifies that dilator activity began and progressed enough even with the low level of stimulation offered by the mild hypopnea. Under these conditions, it would only be a matter of time before the levels required to overcome more severe obstructions are reached.
 
It follows that if a patient opens UA without arousal even once, he/she will have demonstrated an ability to open without arousal under other conditions if arousal does not occur first. That 78% of patients developed type 1 or type 2 response in at least one dial-down (see Figure E6 in the online supplement) implies that the great majority do not need arousal to open the UA.

Only 18 patients (22%) had exclusively type 3 responses. Ten of these, however, developed lengthy periods of stable breathing (> 50% of sleep time) during polysomnography in body positions where dial-downs showed complete obstructions (n = 8) or moderate hypopneas (n = 2). This is unequivocal evidence that a patient can mount effective compensation without arousal. Thus, only eight patients (10%) failed to open the UA without arousal at any time. It is possible that a small minority needs arousal. It is, however, also possible that in such patients arousal threshold was consistently low or that the mechanical abnormalities were sufficiently severe that it was difficult to mount the necessary dilator recruitment without reaching arousal threshold first.

In summary, the present findings indicate that in the vast majority, if not in all, of the patients, arousal is not required for UA opening.

An Alternate Scheme for Relation Between Arousal and UA Motor Control
(A more detailed account of AN ALTERNATE SCHEME FOR RELATION BETWEEN AROUSAL AND UA MOTOR CONTROL is given in the online supplement.)

Figure 10 presents a schema that accounts for current and previous findings. The arousal mechanism (4, 17–22) and UA motoneuron pool (16, 23–29) receive inputs from mechanoreceptors and chemoreceptors. The excitatory input required for arousal (respiratory arousal threshold) varies from time to time and among patients (4, 12, 17, 19, 48, 49) (Figure 10, dashed lines). The excitatory input to UA motor pool required to open the airway (UA opening threshold) varies with severity of mechanical abnormalities (see online supplement). In patients with OSA, the two thresholds are, on average, similar. This accounts for the fact that latency to UA opening is, on average, the same with or without arousal (Figures 3 and 5). However, because the two thresholds are subject to different influences, opportunity exists for UA opening to occur first, and vice versa. By increasing UA opening threshold, more severe obstructions increase probability of arousal occurring first (Figure 4A). Conversely, by increasing arousal threshold, deeper sleep increases probability of UA opening occurring first (Figure 4B).



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  		Figure 10. Schema for relation between arousal and UA opening. Arousal mechanism and UA motoneuron pool receive excitatory input from mechanoreceptors and likely also from chemoreceptors. The amount of excitation required to cause arousal is, on average, the same as the excitation required to activate the UA motoneuron pool enough to independently open UA. However, because the two systems are subject to different influences, the opportunity exists for either event to occur before the other. There are two additional inputs that help enhance the association (synchronizing inputs). When arousal occurs first, an additional excitatory input (Input A) is conveyed to UA motoneuron pool which helps bring it to threshold. When UA opening occurs first, UA opening provides additional arousal promoting inputs (sound, vibration, etc., Input B) that increase the probability of arousal occurring.

 
To the extent that the range of the two thresholds may follow a normal distribution around their average values, the above schema would result in a normal distribution of the relation between Tflow and Tarousal. The distribution of [Tflow - Tarousal] fits this description with two exceptions (Figure 3). First, a second peak exists related to type 1 response. This is readily explained by the fact that when UA opening occurs first mechanoreceptor feedback should immediately decrease even though chemoreceptor input continues to rise for several seconds (circulatory delays). Net excitatory input to arousal mechanism may decrease, or not increase sufficiently, beyond UA opening, thereby averting arousal. Arousal still occurs if the reciprocal changes in the two inputs soon after UA opening result in sufficient increase in net excitatory input to reach arousal threshold (see also DISCUSSION re Input B, below).

Second, the percentage of observations in which Tarousal and Tflow occurred within ± 0.3 seconds of each other (32%, Figure 3) was excessive, suggesting the presence of additional features that help synchronize the two events. Two such features are proposed. Input A (Figure 10): when arousal occurs first, an additional excitatory input is conveyed to the UA motoneuron pool (Figure 10, arrow A). This helps bring this pool to threshold. Such excitatory input cannot be large, however. If it were, UA opening would occur whenever arousal occurred first regardless of how close to threshold UA pool is. This was not the case (Figure 3, bars to right of zero). The current findings (Figure 3) can be explained if Input "A" is proportional to arousal intensity, as supported by data shown in Figure 6. Here, a mild arousal would bring the UA pool to threshold only if excitability of the pool is near threshold. Synchrony is achieved, but there is not much reduction in latency to UA opening. If UA pool were far from threshold, only an intense arousal would succeed in triggering UA opening. Input B (Figure 10): when UA opens before arousal throat vibrations, snoring sound or sudden respiratory unloading provide extra inputs to the arousal mechanism that may bring it to threshold (e.g., Figure 2B).

The main difference between the proposed schema (Figure 10) and current concepts is in the emphasis placed on Input A. At present it is believed that Input A is essential in the vast majority of events. In the current schema, reflex mechanisms are independently capable of opening UA. Input A is only a relatively weak synchronizing input. UA opening would occur at approximately the same time regardless of whether and when arousal occurred.

Pattern of Flow Response at UA Opening
(A more detailed account of PATTERN OF FLOW RESPONSE AT UA OPENING is given in the online supplement.)

One of the most distinctive features of obstructive events is the abruptness with which they end. This clearly suggests a discrete event at UA opening. When coupled with arousal, the impression that arousal caused UA opening is almost unavoidable. In this study, flow increased abruptly whether or not arousal was present. The increase in flow in Breath 1 without arousal was 0.30 ± 0.24 L/second (Figure 6), larger than total flow demand (116 ± 26% of VT/TI on CPAP), with little further increase unless arousal occurred (Figure 7). Thus, an abrupt increase in flow need not reflect a discrete neurological event such as arousal.

The mechanism of abrupt increase in flow in the absence of arousal is not clear. It could be neurogenic, mechanical, or both. A neurogenic mechanism would entail a reflexly mediated disproportionate (versus time) increase in dilator activity at UA opening. A mechanical mechanism would produce this effect if the relation between rising dilator activity and UA area were discontinuous, for example, because of viscid secretions between apposed surfaces. Further studies are needed to clarify the mechanism (see online supplement for additional discussion).

Impact of Arousals on Magnitude of Flow Response
Flow response was higher when arousals occurred (Figures 6 and 7). Possible mechanisms include: (1) Arousal provides an excitatory input to UA motoneurons (Input A, Figure 10) (50, 51). (2) Diaphragm activity increases during transient arousal (32, 52, 53). This would have no effect if flow were limited to a very low level. However, if maximum flow were to increase sufficiently through the first mechanism, the arousal-induced increase in diaphragm activity would increase flow further. The magnitude of this effect was directly related to arousal intensity (Figure 6). Thus, arousal intensity is an important determinant of magnitude of ventilatory overshoot and, by extension, likelihood of recurrent cycling. The ideal response at UA opening is one in which flow rises to a level just below baseline flow but remains limited. In this fashion, some increase in chemical drive (i.e., negative intrathoracic pressure) and high UA resistance are maintained. This combination is required to generate a negative pharyngeal pressure sufficient to maintain UA dilator activity at an adequate level, thereby making it possible to attain a steady state. A flow overshoot at UA opening reduces the chance that PCO2 at the end of the ventilatory phase will be higher than unloaded steady-state PCO2, and it may in fact be lower. The lower the chemical stimulus at the end of the ventilatory phase the higher the likelihood that stimulus for dilator activation will become inadequate causing recurrence of obstruction.

Is the Arousal-related Increase in Flow Helpful or Harmful?
It may be argued that if arousal is not necessary for UA opening it is necessary to obtain adequate flow. Current results show that this is not true. Without arousal, flow response during Breath 1 was, on average, 180% of the initial decline (Figure 6, see also Figure E8B in the online supplement). Thus, without arousal there was already an overshoot corresponding to 80% of the initial decline. With arousal, the overshoot was substantially larger (Figures 6 and 7). This cannot be helpful (30–33). (See "Impact of Arousals on Magnitude of Flow Response," above.) That this is so is supported by the observation that the second hypopnea was more severe when arousal occurred during the first ventilatory response.

Do these observations mean that if arousals did not occur there would be no OSA? The answer is clearly no. Large overshoots and subsequent undershoots also occurred without arousal. The current data, however, indicate that the likelihood for self-perpetuating cycling should be reduced if arousals did not occur. The extent to which arousals are responsible for cycling is difficult to ascertain. However, indirect evidence suggests that they play an important role in most patients. The occurrence of periods of stable breathing in the majority of patients with OSA (9) indicates that most patients can mount stable compensation without arousal. Periods of stable breathing tend to occur as sleep deepens. As indicated earlier, deeper sleep neither reduces UA collapsibility nor alters the dynamics of the compensatory response. Thus, the most reasonable explanation is that when arousal threshold is low, arousals preempt orderly compensation and, by augmenting the overshoot, perpetuate cycling. As arousal threshold rises, arousal is delayed, permitting an orderly compensation by reflex mechanisms.

Sensitivity of Mechanisms Responsible for UA Opening
Latency to UA opening, with or without arousal, was 18.1 ± 10.6 seconds. Because dial-downs began from a stable baseline on CPAP, it is possible to estimate the changes in chemical drive, relative to unloaded levels, required for UA opening. An increase in chemical drive underlies the increase in both the chemo- and mechanoreceptor stimuli because mechanoreceptor feedback cannot increase unless pump muscle pressure increases. Latency to Tflow was within one circulation time (~ 50–60 seconds) in all but a few (~ 1%) dial-downs. Thus, the maximum increase in PaCO2 at Tflow would be the arteriovenous PCO2 difference (4–6 mm Hg). Chemoreceptors would be exposed to a fraction of that because of transport and diffusion delays. Thus, the increase in PCO2 at the peripheral chemoreceptors at Tflow was likely no more than 2 to 3 mm Hg, and the change at central chemoreceptors was even less. O2 saturation decreased, on average, by 3.1 ± 3.5%. These estimates suggest that the mechanisms responsible for UA opening are remarkably potent in most patients, with or without arousal.

REM Sleep
(A more detailed account of REM SLEEP is given in the online supplement.)

When compared at the same min, type 3 responses were more common in REM sleep (Figure 4A). With occlusions, there were virtually no type 1 responses (Figure 4A). This suggests that the balance between arousal threshold and UA opening threshold (Figure 10) is altered in favor of earlier arousal. The frequency of different response types was similar in REM and NREM sleep when compared at the same delta power (Figure 4B). Thus, in REM sleep the balance between the two thresholds is comparable to stage 1 NREM sleep. The unfavorable balance may be due a lower arousal threshold to airway obstruction (54, 55) and/or to inhibitory inputs to UA motoneuron pool during REM sleep (15, 51, 56, 57) (Figure 10, open arrow). The latter would increase the amount of excitatory input required to reach UA opening threshold, effectively increasing this threshold.

The greater likelihood of arousals in REM may explain why some patients have OSA only in REM sleep (58, 59). If arousal threshold is lower than UA opening threshold by a small amount in REM, the balance between the two thresholds may be reversed in NREM sleep because of generally higher delta power and lack of REM-related inhibitory inputs to UA motoneurons. Cycling precipitated by arousals would occur in REM but not in NREM.

Implications
That arousal is not necessary for UA opening and likely contributes to OSA severity has some implications.

Risk factors. OSA is a disease of middle-aged and older humans (60). Children and young adults may have less OSA because of generally deeper sleep (61). Likewise, although differences in anatomic severity may account, in part, for why some older humans have OSA, whereas others do not, it is possible that many older subjects suffer from severe mechanical abnormalities but are protected by a relatively high arousal threshold. If so, OSA may legitimately be considered an arousal disorder.

Drug therapy for OSA. Use of sedatives/hypnotics in OSA is severely discouraged primarily because of the conviction that arousals are needed to open the airway and partly because limited trials gave largely negative results (62–65). The current findings should in no way encourage the clinical use of hypnotics in patients with OSA. However, they should be a stimulus to reevaluate the current position and to encourage research into potential benefits of different drugs. Not all patients, if any, may benefit. Theoretically, the ideal patient is one who has some stable breathing time during sleep in the supine position and in whom obstructive events are brief and terminated by arousal. This patient will have proven that he/she can mount effective stable compensation, without arousals, for the most severe anatomic abnormalities he/she encounters (supine position). Likewise, not all drugs that raise arousal threshold should eliminate cycling. A drug that concurrently increases, by the same amount or more, the UA opening threshold (through depression of the UA motoneurons or their input), will simply increase the duration of obstructive events without eliminating cycling. The ideal drug is one that raises arousal threshold while not increasing UA opening threshold as much. In this fashion, sufficient separation between the two thresholds is created to permit orderly compensation by the automatic mechanisms. It is possible that in earlier clinical trials the results were negative because the wrong type of patient or drug was used.

The focus of the current research into pharmacotherapy of OSA is to develop drugs that stimulate UA dilators (66). The present study suggests that not all types of enhancement of dilator responses should be effective and some may be counterproductive. Thus, even without arousal, UA opening occurred in a timely manner and the flow response was already excessive in most cases. Agents that increase sensitivity and gain of UA dilators' response when obstructive apneas–hypopneas occur are not likely to be helpful and may exacerbate the problem by promoting an even greater overshoot. The ideal agent would be one that prevents obstructive events outright by increasing tonic activity of these muscles (i.e., analogous to CPAP) while, at the same time, leaving unchanged or even reducing the response gain to avoid self-perpetuating cycling, should the tonic effect not be entirely effective.

In summary, in the vast majority of patients, if not in all patients, arousal is required neither to initiate UA opening nor to obtain adequate flow. UA opening would occur at approximately the same time regardless of when or whether arousal occurs and the flow response in most patients would still be timely and adequate. Arousals are incidental events that occur when the thresholds for arousal and arousal-independent opening are close to each other, as they appear to be in patients with OSA. By promoting an unnecessarily high flow response at UA opening, arousals help perpetuate cycling and likely exacerbate OSA.


   Acknowledgments
 
The author is grateful to the sleep lab technologists at the Health Sciences Centre in Winnipeg (Wayne Thompson, Warren Shewchuck, Perry Sahni, Colleen Leslie, Tamara Allen, and Tanya Dykes) for conducting the studies and to John Kun for writing computer programs to facilitate the analysis.


   FOOTNOTES
 
Supported by the Canadian Institutes of Health Research.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: M.Y. has no declared conflict of interest.

Received in original form July 24, 2003; accepted in final form December 15, 2003


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