INTRODUCTION

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According to the principles of flow along a collapsible tube, the two major factors involved in upper airway closure in sleep apnea are: the transmural pressure across the upper airway, and the upper airway compliance (1). In this model of sleep apnea the subatmospheric intraluminal pressure during inspiration "sucks" closed the hypotonic pharynx during sleep. However, upper airway occlusion during sleep apnea has been demonstrated in humans in the absence of any subatmospheric intraluminal pressure (2). This circumstantial evidence suggests a possible role for surface tension forces in upper airway occlusion in sleep apnea. To date, the role of surface tension forces in the pathogenesis of obstructive sleep apnea (OSA) has received little attention. In addition, the fact that (OSA) becomes more severe with the passage of time overnight, irrespective of sleep stage or position (3, 4), suggests a possible role for surface tension forces in OSA. This study was designed to test the hypothesis that surface tension forces in the upper airway play a significant role in the pathogenesis of OSA. Direct assessment of upper airway surface tension forces in humans is difficult because of the very small volume of pharyngeal secretions present. Thus, we aimed to assess the importance of upper airway surface tension forces in OSA indirectly, by evaluating the effect of a topical lubricant with a low surface tension applied to the upper airway, on the severity of OSA.

	METHODS

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Ten male patients (age 49 ± 10 yr [mean ± SD]; body mass index [BMI] 31 ± 5 kg/m²) with mild or moderate OSA syndrome defined as subjective daytime sleepiness accompanied by either an apnea index (number of apneas per hour of sleep) greater than 5, or apnea- hypopnea index (AHI; number of apneas and hypopneas per hour of sleep) greater than 10, were selected for study. All patients were diagnosed by overnight polysomnography at the Sleep Disorders Centre, Royal University Hospital, Saskatoon, Canada, and had been using continuous positive airway pressure (CPAP) treatment for a median duration of 8 mo (range 1 to 13 mo). The baseline AHI of these patients was median 16 (range 6 to 39). All patients gave written informed consent to participate in the study. The research protocol and the consent form were approved by the University of Saskatchewan advisory committee on ethics in human experimentation. The study design was a randomized, double blind, placebo-controlled crossover trial of a topical soft tissue lubricant (surface tension 25.4 mN/m at 37° C) on the severity of sleep apnea as assessed by overnight polysomnography. The topical lubricant, phosphocholinamin (Sonarite; Guardian Chemicals, New York, NY), was administered intranasally (0.4 ml in each nostril) by pipette, in the supine position, at lights out and again after 3.5 h on one night, and placebo at identical times on the other. Dose scheduling was based on a pilot study of the lubricant in three patients with OSA, suggesting a duration of action of approximately 4 h for the topical intranasal phosphocholinamin (Figure 1). Phosphocholinamin in an identical leakproof (wax-sealed) transparent pipette, scented with vanilla (as the lubricant had a faint vanilla-like scent) served as placebo. The option of a scented and sealed pipette as placebo, rather than saline or other fluid, was chosen because of concern that addition of such "placebo" fluids to the upper airway could potentially alter the surface tension properties of upper airway mucus.

View larger version (10K): [in this window] [in a new window]   Figure 1.   Pilot study demonstrating the overnight hour-by-hour severity of OSA in three patients after placebo and after lubricant. During the first part of the night, the differences in the AHI between lubricant and placebo treatment, which persisted for 4 h, are clearly demonstrated in the pilot study. Unfortunately, differences in sleep stage (more REM sleep) and body position (supine versus lateral) in the second portion of the night, obscure the observed effect of the lubricant.

Overnight polysomnography was carried out on two consecutive nights in each patient. Polysomnography included electroencephalograms (EEG; C4-A1, C3-A2, and O2-A1 derivations), electro-oculograms (EOG, 2 channels), submental electromyograms (EMG), pulse oximetry, oronasal airflow (oronasal thermistor), chest and abdominal movement (respiratory inductance plethysmography), snore (vibration sensor), and anterior tibialis EMG (Melville Diagnostics Inc., Ottawa, Canada). A position sensor was used to monitor position continuously on-line (Rochester Electro-Medical Inc., Tampa, FL). Sleep and arousals were scored according to conventionally accepted criteria (5, 6), by an experienced polysomnographer. Arousal index was defined as the total number of arousals per hour of sleep, including respiratory and nonrespiratory arousals from sleep.

Patients with nasal obstruction, swallowing difficulties, or any history of aspiration were excluded from study. On the morning after the second sleep study patients were asked to express their preferred treatment (Night 1 or Night 2).

Data Analysis

Paired t testing was used to compare sleep variables on the two nights (SPSS version 6.0; SPSS Inc., Chicago, IL).

	RESULTS

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The arousal index was lower on the lubricant night (mean arousal index 24) than on the placebo night (mean arousal index 32; mean difference 8; 95% confidence interval [CI] 4 to 11; p = 0.001). This difference was a result of fewer respiratory arousals on the lubricant night, as there was no difference in the number of nonrespiratory arousals between the two nights (lubricant 10, placebo 8; mean difference 2, 95% CI 5 to 1, p = 0.16). AHI was lower in all 10 patients after topical phosphocholinamin (mean AHI 14) than after placebo (mean AHI 24; mean change 10; 95% CI 6 to 13; p = 0.0003; Figure 2. This therapeutic benefit was evident in both the supine (lubricant AHI 20, placebo AHI 33; mean difference 13; 95% CI 5 to 20; p = 0.006) and lateral (lubricant AHI 11, placebo AHI 18; mean difference 6; 95% CI 0 to 12; p = 0.05) positions (Figure 3). The beneficial effect of the lubricant treatment was evident in non-rapid eye movement (NREM) sleep (lubricant AHI 14, placebo 25; mean difference 12; 95% CI 6 to 17; p = 0.001) but not in rapid eye movement (REM) sleep (lubricant AHI 15, placebo 18; mean difference 3; 95% CI 4 to 10; p = NS) (Figure 4). Sleep architecture was similar on the two study nights (Table 1).

View larger version (12K): [in this window] [in a new window]   Figure 2.   Individual and aggregate data depicting the severity of sleep apnea on the placebo night and on the lubricant night.

View larger version (9K): [in this window] [in a new window]   Figure 3.   Aggregate data depicting severity of sleep apnea in the lateral position and in the supine position, on the placebo night and on the lubricant night.

View larger version (8K): [in this window] [in a new window]   Figure 4.   Aggregate data depicting severity of sleep apnea in REM sleep and in NREM sleep, on the placebo night and on the lubricant night.

Although the AHI tended to be higher on the placebo night (mean AHI 24) than on the prestudy baseline diagnostic night (mean AHI 17), this difference was not statistically significant (mean change 7; 95% CI 1 to 15; p = 0.07).

When asked after completion of the study which night they preferred, five patients stated that they slept better on the lubricant night, four had no preference, and one patient preferred the placebo treatment night. The blinding procedure was tested after the study by asking each patient to guess which night the active treatment had been given, and which night the placebo. Six patients guessed correctly, and four incorrectly (p = NS).

No adverse events were noted with the use of phosphocholinamin in this study.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

This study demonstrates a consistent modest (mean 42%) reduction in AHI with the use of a topical lubricant applied to the upper airway at night, in patients with mild to moderate OSA. This finding provides indirect evidence that surface tension forces play a significant role in the pathogenesis of upper airway obstruction in patients with OSA; and implies a potential therapeutic role for topical surface tension reducing agents in the treatment of patients with OSA.

The pathogenesis of OSA is complex and many factors are involved (7). Nonetheless, some existing evidence also points to a potential role for surface tension forces in the pathogenesis of upper airway occlusion. Issa and Sullivan (84) using a closed CPAP circuit, demonstrated in patients with OSA that a subatmospheric upper airway pressure was needed to close the upper airway, but that a subsequent return to atmospheric pressure did not open an already closed airway (8). Badr and colleagues (2) employed nasopharyngoscopy during central apneas on sleeping patients with central sleep apnea (CSA) and normal subjects, and discovered that complete pharyngeal occlusion occurred in 146 of 160 spontaneously occurring central apneas, when there was no subatmospheric intraluminal upper airway pressure (2). These findings strongly suggest that additional factors, such as surface adhesive forces between apposing mucosal surfaces, may contribute to airway closure and may oppose restoration of patency in an occluded upper airway. How would surface tension forces contribute to closure of an already patent upper airway? We already know that surface tension forces contribute to collapse of patent airspaces in the lung, in the absence of surfactant. The mechanism we postulate in the upper airway may be likened to a zipper being fastenedopposing surfaces at the lateral aspects of the upper airway adhere and the upper airway is then closed, starting laterally and working medially, like a zipper being fastened. The endoscopic pictures of upper airway closure detailed by Badr and colleagues (2) would support this view.

This study is the first to document the effect of a topical upper airway lubricant on AHI in sleeping humans with OSA. Van der Touw and colleagues, however, have recently demonstrated that the addition of a synthetic lung surfactant preparation into the supraglottic airway helped in preventing upper airway collapse and facilitated opening of the upper airway in five awake normal supine subjects (9). Others have examined the role of surface tension reducing agents in altering upper airway physiology in animals. Topical application of a synthetic lubricant to the upper airway (isolated by cervical transection) of nine anesthetized dogs significantly reduced the frequency of genioglossal electrical stimulation required to reopen the occluded upper airway (10). The addition of exogenous lubricant had a similar tendency to enhance the patency of the isolated canine upper airway (11, 12), but the beneficial effect in the case of surfactant lasted only 3 to 19 min (11).

The authors did not test the effect of adding saline or other fluids on upper airway patency. Indeed, the effect of simple hydration of the upper airway mucosal surface on upper airway patency has not yet been clarified. Saline decreased the upper airway resistance in anesthetized dogs but did so less consistently than the surface active agent used in the same experiments (12). However, application of saline into the supraglottic airway did not influence the opening and closing airway pressures, or the pharyngeal diameter, in awake supine normal subjects (9).

The beneficial effect of phosphocholinamin was evident in NREM sleep but not in REM sleep in our study. One possible explanation for this finding is that the pathophysiology of OSA may be different in these two distinct sleep states (REM and NREM). Many aspects of respiratory physiology are altered on transition from NREM to REM sleep, with an increased tendency to upper airway collapse during REM sleep (13, 14). The breathing pattern is highly variable during REM sleep (15), and uncoupling of upper airway dilator and thoracic pump muscles at low levels of ventilation increases the tendency to upper airway collapse (16). In addition, a much greater reduction in upper airway dilator muscle activity occurs during REM sleep than in NREM (17, 18). As a result of these physiological changes, the relative contribution of surface tension forces to upper airway occlusion may be much smaller in REM than in NREM, with upper airway dilator muscle hypotonia playing a greater role in REM sleep.

One potentially confounding factor in this study is that OSA is often less severe on the first night after discontinuing CPAP (19). However, in our study the AHI on Nights 1 (mean AHI 20) and 2 (mean AHI 17) were similar (mean change 3; 95% CI 4 to 10, p = 0.4). Prestudy CPAP compliance, another potentially confounding factor for the same reason, was similar between those patients randomized to receive lubricant on Night 1 and those randomized to receive placebo on Night 1.

Phosphocholinamin has some chemical similarity to human surfactant. It is a complex derived from the action of pure lecithin on a light hydrocarbon fraction (mineral oil) (20). Unlike surfactant which is washed away quickly by saliva, however, phosphocholinamin is slowly hydrated by saliva and then becomes dispersible. It thus has a duration of action of several hours (20). Phosphocholinamin, administered as nose drops only once at lights out, significantly reduced the overnight severity of snoring in a group of six snorers, as compared with water in the placebo group (20). The latter study did not, however, record subjects' sleep or respiratory events. Phosphocholinamin has a low surface tension (25.4 mN/m at body temperature 37° C). This is even lower than the equilibrium surface tension of secretions in the tracheobronchial airways of large mammals (31.1 ± 1.5 mN/m), measured in situ (21). Similar values for the surface tension of airway secretions have been reported in vivo in smaller mammals such as hamsters (32.2 ± 2 mN/m) (22), and also in vitro, in excised rat lungs (29.7 ± 1.4 mN/m) (23). Other groups of investigators reported much higher surface tension values for the human bronchial secretions, when the samples were characterized ex vivo, using different (platinum ring or contact angle) methods (24, 25). Thus, two very desirable properties of phosphocholinamin are its low surface tension and prolonged duration of action. However, aspiration of mineral oil poses a risk for lipoid pneumonia (26) and would preclude use of the current formulation over prolonged periods. Nonetheless, the efficacy of this agent in reducing the severity of OSA holds potential promise for similar nonmineral oil based lubricants in the treatment of OSA. Such agents could have a role either as monotherapy in very mild OSA or, in combination with other existing treatments, in more severe sleep apnea.

We conclude that phosphocholinamin, a topical soft tissue lubricant, significantly reduces the severity of OSA in patients with mild-moderate disease. This finding provides indirect evidence that surface tension forces play an important role in the pathogenesis of upper airway occlusion in OSA. Furthermore, the demonstrated benefit of a topical soft tissue lubricant points to a potential role for similar agents in the treatment of OSA in the future.