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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 965-971, (2002)
© 2002 American Thoracic Society

Original Articles

The Effect of Upper Airway Obstruction and Arousal on Peripheral Arterial Tonometry in Obstructive Sleep Apnea

Christopher P. O'Donnell, Lawrence Allan, Paul Atkinson and Alan R. Schwartz

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Christopher P. O'Donnell, Ph.D., Room 4B61, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: codonnel{at}jhmi.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We evaluated the effects of airflow limitation and arousal on digital vascular tone in 10 patients with obstructive sleep apnea (OSA) using the recently developed, noninvasive technique of peripheral arterial tonometry (PAT). Subjects were maintained at a therapeutic level of continuous positive airway pressure, and nasal pressure was acutely dropped for three to five breaths during nonrapid eye movement sleep over a range of pressures from 9.3 ± 1.3 to 1.9 ± 1.3 cm H2O, leading to increasing airway obstruction and decreasing levels of inspiratory airflow. In the absence of a detectable electroencephalographic (EEG) arousal, severe reductions of inspiratory airflow to below 200 ml/second caused significant decreases in PAT amplitude (1.000 ± 0.007 to 0.869 ± 0.007 arbitrary units; p < 0.001), whereas mild airflow limitation (> 200 ml/second) had no effect (1.000 ± 0.009 to 1.011 ± 0.007 arbitrary units). The presence of an EEG arousal accentuated the response to airflow obstruction, such that the PAT amplitude decreased more (p < 0.001) in the presence of arousal (1.000 ± 0.007 to 0.767 ± 0.010 arbitrary units) than in the absence of arousal (1.000 ± 0.007 to 0.923 ± 0.007 arbitrary units). We conclude that airflow obstruction in patients with OSA causes an acute digital vasoconstriction that is accentuated in the presence of an EEG arousal.

Key Words: arterial hemoglobin saturation • autonomic nervous system • continuous positive airway pressure • nonrapid eye movement sleep


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The severity of sleep-disordered breathing covers a spectrum from complete upper airway obstruction, with significant oxyhemoglobin desaturation and arousal, to mild hypopneas, with minimal arterial oxyhemoglobin desaturation and no arousal (1, 2). Several studies indicate that severe obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality (3–6). Recent epidemiologic studies, however, demonstrate that even mild OSA represents an increased risk for the development of systemic hypertension (7). This association between mild OSA and hypertension suggests that hypopneas, or even periods of flow limitation that do not meet thresholds for counting as sleep-disordered events, may have cardiovascular consequences. However, our current clinical techniques may not be adequate for detecting subtle cardiovascular changes in response to more mild forms of OSA.

The autonomic nervous system plays a key role in mediating the cardiovascular changes in OSA (8–14) and may act as a marker of even subtle cardiovascular changes associated with flow limitation. A number of factors may alter output from the autonomic nervous system in response to the physiologic disturbances that characterize periods of upper airway obstruction. Hypoxia, acting through the carotid body, can increase sympathetic nerve activity (SNA) to peripheral blood vessels causing vasoconstriction (8, 9, 15). Any changes in SNA that occur in response to hypoxia may be further modified by the hypercapnia and the cessation of breathing that accompany obstructive apneic events (8, 16–20). In addition, in sleep-disordered breathing events terminated with arousal, SNA is increased to the peripheral blood vessels and heart (21–24). It is currently unclear, however, to what extent arousal per se can increase SNA and whether periods of flow limitation with minimal oxyhemoglobin desaturation and no arousal can also increase SNA to the peripheral vasculature in OSA.

The recently developed technique of peripheral arterial tonometry (PAT) allows noninvasive assessment of vasoconstriction in the finger as a marker of SNA to the peripheral vasculature (25–27). The PAT device consists of a specially designed finger pneumo-optic plethysmograph. The pulse waveform of the PAT signal has been shown previously to decrease transiently in patients with OSA with a timing and periodicity linked to the arterial oxyhemoglobin desaturation and arousal response of the apneic cycle (26). These data suggest that the PAT signal is sensitive to the increase in SNA to the periphery that is associated with obstructive apneic events.

The purpose of the present study was to separate the arousal response from the preceding apnea/hypopnea and systematically determine the contribution of each of these two components to changes in the PAT signal in a group of patients with OSA. We adapted a protocol developed in our canine model to study the acute cardiovascular effects of OSA. In the canine model, the period of induced airway obstruction was controlled by the worker such that apneic events, matched for duration and oxyhemoglobin saturation, were terminated either with or without a detectable electroencephalographic (EEG) arousal response (21, 22). Analogously, in the present study, continuous positive airway pressure (CPAP) was dropped from a therapeutic level in patients with OSA to induce acute periods of upper airway flow limitation for three to five breaths. The effect of arousal was examined by comparing periods of airflow obstruction during sleep in which apneic/hypopneic events, otherwise matched for duration and oxyhemoglobin desaturation, were terminated either with or without an EEG arousal response. We hypothesized that airflow obstruction during nonrapid eye movement (NREM) sleep would cause digital vasoconstriction (decreased PAT amplitude), even in the absence of an EEG arousal response. In addition, we hypothesized that the PAT amplitude would be further reduced in response to periods of airflow obstruction that resulted in an EEG arousal from NREM sleep.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subject Selection
A total of 10 CPAP-treated patients recruited from the Johns Hopkins Sleep Disorders Center were studied. All patients were CPAP treated (range 6–24 months). Informed consent was obtained from each subject for this protocol, which had been approved by the Human Investigation Review Board of our institution. They were considered eligible if the respiratory disturbance index during NREM sleep was greater than 10 episodes/hour. Patients with any concurrent medical illnesses except hypertension were excluded. A baseline polysomnogram was performed to characterize sleep apnea as defined by standard techniques previously described (28).

Study Design
Each patient underwent baseline full-night polysomnography (PSG) to characterize the severity of sleep-disordered breathing during NREM and rapid eye movement (REM) sleep (see BASELINE PSG subsequently). Thereafter, patients underwent an additional night study to assess changes in digital vascular tone during periods of acute airflow obstruction in NREM sleep (see EXPERIMENTAL PROTOCOL subsequently).

Baseline PSG
Recording methods. Standard PSG techniques were used to characterize patients at baseline and during the experimental protocol. In brief, physiologic variables were continuously recorded including EEG (C4/A1, C3/A2), electrooculogram, chin muscle electromyogram and electromyogram of anterior tibialis muscle, and ECG. Snoring was measured with a microphone placed at the suprasternal notch. A body position sensor attached to a thoracic belt was used to monitor body position. Oxygen saturation was measured by pulse oximetry (Palco Laboratories; Santa Cruz, CA). Tidal airflow was monitored with a thermocouple or full-face mask connected to a pneumotachometer (279331; Hamilton Medical; Reno, NV). A balloon probe (Medtronic Upper Airway; Maastricht, The Netherlands) connected to a pressure transducer (Response III; Medtronic Upper Airway; Minneapolis, MN) measured esophageal pressure as previously described. The signals from the esophageal balloon were used to measure respiratory effort. All physiologic signals were digitized at a frequency of 100 Hz and stored for further analysis (Windaq/200; Dataq Instruments; Akron, OH).

Analysis. Sleep stage analysis of nocturnal PSG was performed visually according to the criteria outlined by Rechtschaffen and Kales (29). A 3-second definition for arousal was used, as per the American Academy of Sleep Medicine. Apnea was defined by the complete absence of oronasal airflow for at least 10 seconds. Apneas were classified as obstructive, mixed, or central according to standard criteria. Hypopnea was defined as a greater than 50% decrease in oronasal airflow accompanied by a 4% drop in oxygen saturation from baseline or an EEG arousal from sleep. The apnea/hypopnea index was calculated as the total number of apneas and hypopneas per hour of sleep for both NREM and REM sleep, and separately for the time that the patient slept supine and in the lateral recumbent position.

Experimental Protocol
Each patient was fitted with a finger plethysmograph for measurement of the PAT (PAT; Itamar Medical, Caesaria, Israel) signal (25–27). The PAT device is based on a specially designed finger pneumo-optic plethysmograph measuring arterial pulsatile blood volume changes at the fingertip. The pneumo-optic finger plethysmograph is composed of two interconnected, parallel halves of a longitudinally split thimble, which generates a subdiastolic uniform pressure field surrounding the whole surface of the two distal phalanges of the finger and a set of optical transmitter/receiver devices that measure optical density changes. Pressure within the device is derived from a self-contained, pressurized, elastic reservoir, and is independent of finger volume. The uniform pressure field, of the order of 50 mm Hg, serves to (1) improve the dynamic range of the signal by unloading finger arterial wall tension, (2) prevent venous blood pooling at the finger tip that may cause venoarteriolar reflex vasoconstriction (30), and (3), by extending proximally before the measurement site, provide a buffering effect that prevents artifacts caused by retrograde propagation of mechanical perturbations via the venous blood. The optical signal is electrically coupled and band-pass filtered between 0.25 and 25 Hz.

Patients were fitted with a nasal mask (nasal CPAP mask; Respironics Inc; Murraysville, PA), and a chin strap was used to minimize leakage of air through the mouth when necessary. Airflow was measured with a pneumotachometer that was connected to the nasal mask and a pressure transducer (Sefam; Vandoeuvre-les-Nancy, France). Nasal pressure (Pn) was measured with a similar pressure transducer connected to a port in the nasal mask. The nasal mask was connected via a breathing circuit and a bidirectional valve to a positive pressure source (Tranquility Plus; Healthdyne Technologies; Marietta, GA) and a negative pressure source (modified Rem-Star unit; Respironics). Pn was set within the positive range by altering the flow delivered by the CPAP device through the breathing circuit. When Pn was lowered into the negative pressure range, the level of subatmospheric pressure was preset in the negative pressure source. The bidirectional valve was then switched, thereby connecting the negative pressure source to the breathing circuit. Thereafter, the valve was switched back to restore a positive Pn. Physiologic signals from the PAT device, the pneumotachograph, and Pn were digitized at a frequency of 100 Hz and stored for further analysis (Windaq/200; Dataq Instruments).

During the experimental protocol, each patient was allowed to initiate sleep, and Pn was increased stepwise every 5 minutes as previously described (31) until inspiratory airflow (I) limitation was abolished. The holding pressure was then defined as the lowest level of Pn required for eliminating I limitation. This pressure corresponded to the minimal "effective CPAP pressure" and to the "upper airway opening pressure," as previously described by other investigators (32). This level of holding Pn was then maintained throughout the protocol.

During periods of stable NREM (Stages II–IV), Pn was lowered abruptly during an inspiration for a period of three to five breaths and thereafter was raised back to holding pressure (33). The Pn was decreased in a randomized fashion to reduce airflow over a range from no airflow limitation to at or near complete airflow obstruction. If arousal occurred, the patient was allowed to reestablish stable NREM sleep before continuing the experimental protocol. Runs spanned a range of approximately 6–8 cm H2O in Pn and a range of zero to approximately 500 ml/second in maximal I.

In six subjects, at the completion of the protocol during sleep described previously, a comparable series of Pn drops was made in wakefulness, during which I limitation was not present. This protocol acted as a control for any nonspecific effects of acute decreases in Pn on PAT amplitude that occurred independent of I limitation.

Data Analysis
With each step decrease in Pn, PAT amplitude and heart rate were averaged during three periods as follows (see Figure 1) : P1, the period representing the 10 cardiac cycles immediately before the drop in Pn; P2, the period representing the 10 cardiac cycles immediately before Pn being restored to holding pressure; and P3, the period representing the first 10 cardiac cycles after Pn is restored to holding pressure. For each drop in Pn, PSG signals were examined and an agreement was reached between two trained polysomnologists as to the presence or absence of a detectable EEG arousal based on standardized criteria according to the ASDA (34)—namely, an EEG frequency shift of 3 seconds or greater duration, either with or without concurrent increases in submental EMG amplitude. In addition to the PAT amplitude and heart rate analyses described previously, the duration, I, and associated arterial hemoglobin desaturation was assessed for each drop in Pn.



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  		Figure 1. A representative tracing from one subject showing the changes in PAT during periods of mild inspiratory flow limitation without a detectable EEG arousal (left panel), severe inspiratory flow limitation without a detectable EEG arousal (middle panel), and severe inspiratory flow limitation with arousal (right panel). L. EOG = left electrooculogram; C3-A2 = EEG placement; , Pn = nasal pressure; Pes = esophageal pressure; P1, P2, and P3 represent periods of 10 cardiac cycles preceding the decrease in Pn (P1), at the end of the period of decreased Pn (P2), and immediately after Pn is restored to the holding pressure (P3).

 
Analysis of variance was used to detect significant differences in outcome variables of PAT amplitude and heart rate. Two-way analysis of variance was used to determine differences in PAT amplitude and heart rate across conditions of period (P1, P2, and P3) and arousal (arousal, and no arousal). One-way analysis of variance was used to determine differences in PAT amplitude and heart rate across the condition of airflow obstruction (> 200 ml/second, mild obstruction; 0–200 ml/second, severe obstruction) for drops in Pn that were not associated with an arousal. A p value less than 0.05 level of significance was used, and data are reported as means ± SD.

The reproducibility of changes in PAT amplitude in response to airflow obstruction and arousal was determined by calculation of (1) the coefficient of variation and (2) the Pearson's correlation coefficient for repeated measurements within subjects. The coefficient of variation (SD/mean) was calculated during severe airflow obstruction (0–200 ml/second) either with or without an EEG arousal as the change in PAT for subjects with three or more repeated measurements. The Pearson's correlation coefficient was calculated during severe airflow obstruction (0–200 ml/second) either with or without an EEG arousal as the change in PAT from the first two repeated measurements in each subject.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Population
Subjects consisted of one female and nine male patients with predominantly OSA. Anthropometric data and results of the baseline polysomnographic study are shown for individual subjects in Table 1 . Of the 11 subjects, 5 were on antihypertensive medication (diuretic, 2; central agent, 1; ß-blocker, 2; angiotensin-converting enzyme inhibitor, 4; calcium-channel blocker, 1).


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  		TABLE 1. Anthropometric data and baseline polysomnographic data for 10 subjects

 
Reproducibility of PAT Response
The coefficient of variation for repeated measurements of the PAT response to severe airflow obstruction (0–200 ml/second) was 6.8 ± 3.9% for the group as a whole. Repeated measurements of the PAT response to severe airflow obstruction were significantly correlated (r = 0.93; p < 0.001) for the group as a whole.

Pn Drops
The therapeutic Pn averaged 13.1 ± 1.1 cm H2O in the 10 subjects, and the range over which Pn was acutely dropped averaged 9.3 ± 1.3 to 1.9 ± 1.3 cm H2O. The Pn was dropped acutely 13.1 ± 5.8 times per subject (range 7–24) for a duration of 14.2 ± 3.9 seconds, resulting in 91 apneic/hypopneic events without an arousal response and 40 apneic/hypopneic events with an arousal response.

Effect of Airflow Obstruction in the Absence of an EEG Arousal
Figure 1 (left panel) is a sample trace showing a step reduction in nasal airflow from 17.2 to 9.5 cm H2O during NREM sleep. The drop in Pn reduced inspiratory flow to 463 ml/second and resulted in augmented esophageal pressure swings. The PAT signal remained constant before (P1), during (P2), and after (P3) the period of mild I limitation. A more severe period of upper airway obstruction without an EEG arousal is shown in Figure 1 (middle panel) in which the Pn decreased to 5.4 cm H2O during NREM sleep and reduced inspiratory flow to 25 ml/second. The PAT signal remained constant during periods P1 and P2, but decreased during period P3, despite the absence of an arousal response.

For pooled data from all subjects (Table 2) , the airflow averaged 81 ± 10 ml/second during severe inspiratory flow limitation (Imax < 200 ml/second) and 378 ± 14 ml/second during mild inspiratory flow limitation (Imax > 200 ml/second). The more severe inspiratory flow limitation was associated with events of shorter duration but greater arterial hemoglobin desaturation (p < 0.0001). The changes in PAT amplitude for mild and severe I limitation in response to drops in Pn without an EEG arousal are shown in Figure 2 . There was an overall significant interaction (p < 0.0001) between the degree of airflow limitation and the period (P1, P2, P3), such that the amplitude of the PAT signal decreased more in response to severe inspiratory flow limitation than mild inspiratory flow limitation. Similarly, there was a small but significantly higher (p < 0.05) heart rate in response to severe inspiratory flow limitation compared with mild inspiratory flow limitation.


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  		TABLE 2. Arterial hemoglobin saturation for two levels of inspiratory airflow limitation*

 


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  		Figure 2. Mean (± SD) amplitude of PAT during periods of mild and severe inspiratory flow limitation that did not cause a detectable EEG arousal; P1, P2, and P3 represent periods of 10 cardiac cycles preceding the decrease in Pn (P1), at the end of the period of decreased Pn (P2), and immediately after Pn is restored to the holding pressure (P3). As indicated, a significant interaction exists between periods of airflow limitation (P1, P2, and P3) and level of flow limitation (mild, severe) as determined by two-way analysis of variance.

 
Effect of Arousal Induced by Periods of Upper Airway Obstruction
Figure 1 (right panel) is a sample trace showing a step reduction in Pn from 17.2 to 5.5 cm H2O during NREM sleep. The abrupt drop in Pn led to a marked decrease in tidal airflow (30 ml/second), augmented esophageal pressure swings, and arousal from sleep. The PAT signal remained stable during the period of reduced Pn (P2 versus P1), but attenuated markedly during arousal from sleep (P3). The reduction in the PAT amplitude was greater in the presence of an EEG arousal (Figure 1; right panel) than during a comparable decrease in Pn and airflow without an EEG arousal in the same subject (Figure 1; middle panel).

For all 10 subjects, the duration of the fall in Pn was not different between events with arousal (14.2 ± 4.0 seconds) and without arousal (14.2 ± 3.7 seconds). Similarly, there was no difference in the fall in SaO2 in response to events with arousal (2.6 ± 1.7%) when compared with events without arousal (2.1 ± 1.5%). However, the level to which Pn decreased was significantly less (p < 0.0001) in events with arousal (2.2 ± 4.7 cm H2O) when compared with events without arousal (6.0 ± 4.2 cm H2O). Consequently, the airflow through the upper airway was also less (p < 0.05) in events with arousal (133 ± 145 ml/second) when compared with events without arousal (202 ± 175 ml/second).

Pooled data in Figure 3 show the change in PAT signal across periods P1, P2, and P3 for Pn drops with and without arousal. Analyses by two-way analysis of variance showed an overall significantly lower PAT for the arousal compared with the no arousal condition (p < 0.001) and a significant interaction between arousal and period (p < 0.001), such that the decrease in PAT from periods P1 through P3 was accentuated in the presence of arousal. During period P3, the PAT amplitude was 0.923 ± 0.007 relative to baseline (P1) in the no arousal condition, whereas during the arousal condition the PAT amplitude was reduced to 0.767 ± 0.010 by period P3.



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  		Figure 3. Mean (± SD) amplitude of PAT in response to periods of airflow obstruction that are associated either with or without a detectable EEG arousal; P1, P2, and P3 represent periods of 10 cardiac cycles preceding the decrease in Pn (P1), at the end of the period of decreased Pn (P2), and immediately after Pn is restored to the holding pressure (P3). As indicated, a significant interaction exists between periods of airflow limitation (P1, P2, P3) and arousal (present or absent) as determined by two-way analysis of variance.

 
Comparable analyses by two-way analysis of variance revealed that heart rate was higher (p < 0.0001) in the arousal (69.2 ± 0.5 bpm) compared with the no arousal condition (63.4 ± 0.3 bpm), and there was a significant interaction between arousal and period, such that the increase in heart rate from periods P1 through P3 was accentuated in the presence of arousal.

In a subanalysis, we compared the PAT amplitude only during periods of severe inspiratory flow limitation (Imax < 200 ml/second) in the presence and absence of arousal. Table 3 shows that such a subanalysis resulted in comparable reductions in airflow between the arousal and no arousal condition, in contrast to the higher levels of airflow seen when all no arousal data where pooled (202 ± 175 ml/second, as in the foregoing). With the subanalysis a significant interaction was still present between arousal and period (p < 0.001), with the PAT amplitude decreasing to a lower level in the arousal condition (0.767 ± 0.010) than in the no arousal condition (0.869 ± 0.010).


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  		TABLE 3. Arterial hemoglobin saturation during nasal pressure drops*

 
Effect of Airflow Obstruction During Wakefulness
To account for any nonspecific effects of abruptly dropping Pn on PAT amplitude and heart rate, we examined responses during wakefulness in the absence of airflow limitation. In six subjects, Pn was decreased on average 4.7 ± 1.9 times (range 2–7 Pn drops) to 4.9 ± 3.6 cm H2O for a duration of 25 ± 12.8 seconds, without any significant change in baseline saturation (0.8 ± 1.3%). The PAT did not significantly decrease during periods P1 (1.000 ± 0.011), P2 (0.980 ± 0.012), or P3 (0.978 ± 0.012) in wakefulness, and similarly, there was no significant change in heart rate across periods P1 to P3.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
OSA is associated with acute cardiovascular changes that are mediated largely by changes in SNA to the heart and peripheral vasculature (8–14). In the present study, we have used a novel finger plethysmograph in combination with a technique to acutely manipulate the degree of upper airway obstruction in patients with OSA to determine changes in digital vasoconstriction associated with obstructive apneic events. The data demonstrate two new findings. First, we show that in the absence of a detectable EEG arousal, brief periods of airflow obstruction associated with small decreases in arterial oxyhemoglobin saturation can significantly reduce the amplitude of the PAT signal. Furthermore, the reduction in PAT amplitude was dependent on the degree of airflow obstruction, such that greater airflow obstruction produced greater reductions in PAT amplitude (Figure 2). Second, an EEG arousal, resulting from periods of induced airflow obstruction during NREM sleep, leads to a greater reduction in PAT amplitude compared with comparable levels of airflow obstruction without an arousal (Figure 3). The data in Figure 3 strongly suggest that an EEG arousal, induced by an acute period of airflow obstruction, can independently increase SNA to the peripheral vasculature of the finger. Thus, changes in SNA to the digital vascular bed that occur during sleep in response to upper airway obstruction are potentiated by arousal.

Effect of Airflow Obstruction in the Absence of EEG Arousal
The present study demonstrates that airflow obstruction in sleeping patients with OSA leads to increased digital vasoconstriction in the absence of a detectable EEG arousal. Moreover, the magnitude of the digital vasoconstriction was dependent on the degree of airflow obstruction. Smaller degrees of airflow obstruction (> 200 ml/second; Figure 2) were not associated with any detectable decrease in the magnitude of the PAT amplitude. In contrast, with more severe airflow obstruction (0 to 200 ml/second) the PAT amplitude decreased approximately 15% during the period immediately after the drop in Pn (P3; Figure 2). Thus, in patients with OSA, acute periods of airflow obstruction lead to digital vasoconstriction even in the absence of an EEG arousal response.

It was not within the scope of the present study to determine what mechanisms account for the reduction in PAT amplitude during periods of severe airflow obstruction without arousal. However, two observations from our study are relevant to such a discussion. First, there were no observable fluctuations in the amplitude of the PAT signal corresponding to respiration. Although SNA is known to be modulated by respiration (8, 35), there was no evidence that the PAT signal was sensitive enough to detect such changes. Finger plethysmography measures shifts in blood volume, which is likely to have a longer time course than the respiratory cycle. Thus, respiratory changes related to airflow obstruction do not appear to account for the changes in PAT amplitude seen in the absence of an EEG arousal.

Second, the reduction in PAT amplitude in the absence of an EEG arousal occurred only after the period of airflow obstruction (P3). One explanation for reduced PAT amplitude in period P3 would be that hypoxic stimulation of the carotid body produces increased SNA to the peripheral vasculature causing vasoconstriction. The finding supports such a hypothesis in that only severe airflow obstruction, which was associated with the greatest oxyhemoglobin desaturation (compared with mild airflow obstruction; see Table 2), caused a decrease in the PAT amplitude. Support for a hypoxic vasoconstriction during airflow obstruction is seen in our previous studies of a canine model of OSA in which either hyperoxia or hexamethonium, an autonomic nervous system blocking agent, alleviated the acute hypertension that accompanied induced airway obstruction without arousal (9). However, in the canine study the arterial hemoglobin desaturation was approximately 5–6%, which is at least twice the level of desaturation found at the severe level of airflow obstruction (Table 2) in the present study. Potentially, other neural reflexes related to the airflow obstruction, such as chemoreflex responses to hypercapnia, or lung stretch/chest wall mechanoreceptors, may act to augment the relatively small hypoxic input to the carotid body to produce detectable changes in SNA and PAT amplitude. Finally, it is possible that airflow obstruction resulted in subtle micro-arousals that did not meet ASDA criteria (34) but did result in significant reductions in PAT amplitude. Thus, it is not clear whether minor levels of arterial hemoglobin desaturation, other neural reflexes, or subtle micro-arousals lead to increases in peripheral vascular tone and, therefore, account for the reductions in PAT amplitude that occur in the absence of ASDA-defined arousal.

Apnea-induced EEG Arousal and Digital Vasoconstriction
In patients with OSA, the acute increases in arterial blood pressure and muscle SNA that accompany each obstructive event reach a maximum at the time of arousal (12). Consequently, the arousal response is considered an important contributor to acute elevations in arterial blood pressure in OSA, and surges in SNA to the peripheral vasculature is a potential mediating mechanism (23, 24). The role of SNA in mediating arousal-induced increases in arterial blood pressure has been tested in human subjects aroused from NREM sleep with auditory tones. Auditory arousal from NREM sleep caused significant increases in SNA and arterial blood pressure but not cardiac output, consistent with a mechanism of peripheral vasoconstriction (23). However, the neural inputs mediating an auditory arousal are likely different from the neural inputs mediating an apnea-induced arousal. Multiple inputs from peripheral and central chemoreceptors, lung and airway stretch receptors, chest wall muscle receptors, and potentially many other neural reflexes may contribute to the arousal response from an apnea. As such, cardiovascular responses to auditory and apnea-induced arousal are not necessarily comparable (24). The data presented in the present study indicates that a detectable EEG arousal induced specifically from periods of airflow obstruction during NREM sleep produces a significant reduction in PAT amplitude, consistent with increased digital vasoconstriction. Thus, our current study extends the previous work using auditory tones to show that apnea-induced arousal is associated with digital vasoconstriction in patients with OSA.

Limitations of the Study
Several limitations need to be acknowledged with respect to the present study. First, the findings of the current study are limited to the specific filtering characteristics and pressure properties of the PAT device used (as noted in METHODS). Second, the necessity of obtaining sufficient periods of airflow obstruction without a detectable EEG arousal required that drops in Pn were of relatively short duration (approximately 13–16 seconds). As noted previously, the short duration of the Pn drop led to relatively small decreases in arterial hemoglobin saturation, limiting our ability to examine the relationship between hypoxia and PAT amplitude. Third, the PAT signal is a relative measurement that displayed observable baseline drift over long periods in our patients with OSA. However, the experimental approach in the present study involved an intervention of short duration with a preceding stable baseline period in which flow limitation was abolished by maintaining an elevated Pn. Under such acute, controlled conditions the changes in PAT amplitude are likely to represent reliable changes in digital vasoconstriction. Fourth, direct arterial blood pressure recordings did not accompany our measurement of PAT amplitude. The simultaneous measurement of arterial blood pressure would have confirmed that the changes in finger vascular tone we were measuring resulted in concomitant changes in systemic arterial blood pressure. However, in patients with OSA, a sharp reduction in PAT amplitude is precisely timed to the surge in arterial blood pressure associated with the arousal and hyperventilation phase after an obstructive apneic event (36). Moreover, the changes in digital vascular tone we observed in both the presence and absence of an EEG arousal in patients with OSA are entirely consistent with the mechanistic studies of autonomic nervous system and blood pressure responses in our canine model using an analogous approach (9, 21, 22). Thus, we would expect that the decreases in PAT amplitude that we report would be accompanied by corresponding increases in arterial blood pressure.

Implications
The PAT amplitude provides a reliable method for detecting changes in digital vasoconstriction that occur in response to airway obstruction and arousal from sleep. Previous studies have shown that autonomic stress tests, including the Cold Pressor Test and Mueller Maneuver, as well as administration of norepinephrine, can significantly reduce the amplitude of the PAT signal (37). Moreover, the same studies showed that the PAT amplitude declined less in patients with OSA at end-apnea and arousal after administering the {alpha}-adrenergic blocker phentolamine, suggesting that PAT attenuation is mediated by peripheral vasoconstrictive responses to apnea and arousal. Thus, the PAT signal reflects changes in sympathetic activity acting on {alpha}-adrenergic receptors of the finger vascular bed. As such, our data would suggest that even brief periods of airway obstruction in the absence of an EEG arousal can lead to significant increases in {alpha}-adrenergic mediated digital vasoconstriction.


   FOOTNOTES
 
Supported by National Heart, Lung, and Blood Institute grants HL50381 and HL37379 and Itamar Medical Ltd.

Received in original form October 18, 2001; accepted in final form May 27, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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