INTRODUCTION

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Excessive secretion of growth hormone (GH) by a pituitary micro- or macroadenoma usually causes acromegaly, which is characterized by enlargement of skeletal structures, especially at the distal portions such as the nose, ears, jaws, fingers, and toes (1). This disorder affects 38 to 60 cases per million in both females and males (2). Increased mortality of acromegaly is believed to be due mainly to high prevalence of cardiovascular, metabolic, and respiratory complications such as hypertension, diabetes mellitus, and sleep apnea (3). By studying a relatively large population of patients with acromegaly, prevalence of sleep apnea in acromegaly is estimated to be 17 to 60% (4, 5). Types of apnea during sleep in acromegaly were either central or obstructive according to recent polysomnographic findings (4, 6, 7). Although a positive correlation between GH hypersecretion and prevalence of central apnea in acromegaly implies that control of disease activity may lead to the disappearance of central apnea (4, 8), previous studies reported persistence of sleep apnea even after surgical removal of the pituitary adenoma, presumably because of the presence of obstructive events (8, 9). Accordingly, examination of the site of upper airway obstruction and collapsibility of the upper airway is of great importance. Current knowledge of intrinsic mechanical properties of the upper airway in acromegaly is, however, superficial and controversies exist in terms of the site of obstruction (10). The purpose of the present study is, therefore, to describe the static mechanics of the passive pharynx in active acromegaly with and without sleep-disordered breathing (SDB). Because previous reports strongly suggest different pathogenesis of SDB in acromegaly compared with the ordinary sleep apnea, another aim of this study is to clarify the difference of the mechanical properties of the pharynx between acromegalic SDB patients and nonacromegalic patients with SDB. As reported previously, we designed this study to investigate the intrinsic mechanical properties of the passive pharynx by eliminating neuromuscular factors, which also influence pharyngeal patency (13).

	METHODS

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Subjects

Our study consisted of 10 consecutive patients with acromegaly who were scheduled for transsphenoidal adenomectomy. None of the patients had received treatment for acromegaly prior to the surgery, except Patient 2 who had received bromocriptine. Hormonal activity was evaluated by measurements of serum GH and insulin-like growth factor-1 (IGF-1) levels using radioimmunoassay. Normal ranges of the serum GH and IGF-1 in our institute were < 5 ng/ml, and 106 to 390 ng/ml, respectively. Blood samples obtained on the morning of the surgery evidenced abnormally high levels of GH and IGF-1 (Table 1). Nocturnal disordered breathing was preoperatively evaluated by a pulse oximeter (Pulsox-5; Minolta, Tokyo, Japan) in all patients at least twice during hospitalization. Computer-calculated oximetry parameters such as the oxygen desaturation index (ODI), were defined as the number of oxygen desaturation (measured as Sa_O2) exceeding 4% from the baseline per hour, and the percentage of time spent at Sa_O2 < 90% (CT₉₀). Clinical symptoms suggesting presence of SDB, such as hypersomnolence, heavy snoring, and apnea witnessed by others, were carefully evaluated. Individual characteristics, serum hormone levels, clinical symptoms, and results of nocturnal oximetry are presented in Table 1. Mean age was 49.3 ± 6.4 yr and body mass index (BMI) was 25.0 ± 3.3 kg/m² on average. Patient 2 had had an uvulopalatopharyngoplasty approximately 2 yr before the adenomectomy. The aim and potential risks of the study were fully explained, and informed consent was obtained from each subject. The investigation was approved by the Hospital Ethics Committee.

Preparation of the Subjects

Our unique endoscopic evaluation of static pharyngeal mechanics has been described previously in detail (13). Each subject was initially premedicated with 0.5 mg of atropine 30 min before induction of anesthesia. Each subject was instructed to lie in the supine position on an operating table, with the neck in a comfortable neutral position. A modified tight-fitting nasal anesthetic mask was used. Care was taken to prevent air leaks from the mask, particularly when the airway was pressurized above 20 cm H₂O. The mouth was closed by a chinstrap. General anesthesia was induced by intravenous administration of thiopental sodium (4 mg/kg), and intravenous administration of muscle relaxant (vecuronium, 0.2 mg/kg) achieved complete paralysis throughout the experiment. Anesthesia was maintained by inhalation of sevoflurane (2 to 4%) while the subject was ventilated with positive pressure through use of an anesthetic machine. Continuous monitoring of Sa_O2, electrocardiogram, and blood pressure were also performed. A slim endoscope (FB10X, 3 mm outer diameter; Pentax, Tokyo, Japan) was inserted through the modified nasal mask and the naris. The tip of the scope was placed at the upper airway to visualize the velopharynx (retropalatal space) and the oropharynx (retroglossal space). A closed- circuit camera (ETV8; Nisco, Saitama, Japan) was connected to the endoscope in order to record the pharyngeal images and airway pressures (Paw), measured by a water manometer, on videotape. Surgical procedure followed the endoscopic examination.

Experimental Procedure

In order to obtain static pressure-area relationship of the passive pharynx after disconnection from the anesthetic machine, the nasal mask was connected to a pressure-control system capable of accurately manipulating Paw from 20 to 20 cm H₂O in a stepwise fashion. Cessation of mechanical ventilation resulted in apnea caused by complete muscle paralysis, and immediate increase of Paw to 20 cm H₂O caused airway dilatation. While the subject remained apneic for 2 to 3 min, Paw was gradually reduced in a stepwise fashion from 20 cm H₂O to a velopharyngeal closing pressure, which represents the pressure at which complete closure of the velopharynx occurs, as confirmed on video. The apneic test was terminated at decrease of Sa_O2 under 95%. This experimentally induced apnea procedure allowed the construction of a pressure-area relationship of the visualized pharyngeal segment. The subject was manually ventilated for at least 1 min before and after the apneic test. Distance between the tip of the endoscope and the narrowing site was measured by a wire passed through the aspiration channel of the endoscope.

Data Analysis

In order to convert each image on the monitor to an absolute value of cross-sectional area of the pharynx, magnification of the imaging system was estimated at 1.0-mm intervals between the tip of the endoscope and the object in the range of 10 to 30 mm. The pharyngeal image on the monitor at a determined Paw was outlined on tracing paper (50 g/m²), and the weight of the paper cut along the trace was measured by a scale (ER120A; AND, Tokyo, Japan). The weight was converted to square centimeters of the pharyngeal area according to the magnification. For a constant distance, the area measurements were validated to be accurate within 8% (range, 0.1 ± 4.6%; +6.5 to 7.6%) by tubes of a known diameter (4 to 9 mm interior diameter).

The measured luminal cross-sectional area was plotted as a function of Paw. At high values of Paw, cross-sectional areas were relatively constant and maximal area (Amax) was determined as the mean value of the measured area of the highest three Paw (18, 19, and 20 cm H₂O). As reported previously, the pressure-area relationship of each pharyngeal segment was fitted by an exponential function, A = Amax  B · exp(K · Paw), where B and K are constants. A nonlinear least-square technique was used for the curve fitting, and the quality of the fitting was provided by coefficient r² (SigmaPlot version 2.0; Jandel Scientific Software, San Rafael, CA). A regressional estimate of closing pressure (P'close) was calculated from the following equation for each pharyngeal segment: P'close = ln(B/Amax)K¹. K represents the shape of the curve independent of maximal area, and stiffness of the pharyngeal segment is considered to increase with decreasing K values.

Collection of Static Pharyngeal Mechanics Data from a Group of Nonacromegalic Patients with SDB

In order to characterize static pharyngeal mechanics of SDB patients with acromegaly in contrast to those without acromegaly, we sampled age-, BMI-, and ODI-matched ordinary SDB patients from our accumulated patients' data source, partly including previously reported data (14, 15). Of 70 symptomatic SDB patients who had ODI greater than 10 h¹, and had endoscopic evaluation of the static mechanical properties of the pharynx in our laboratory, 18 patients had the same ranges of age, BMI, and ODI (Table 2). We compared static mechanical variables between acromegalic patients with ODI greater than 10 h¹ and these SDB patients without acromegaly.

Statistical Analysis

All values were expressed as mean ± SD. Comparison of the mechanical variables between the pharyngeal segments and comparison of body habitus, oximetry, and mechanical parameters between SDB patients with acromegaly and those without acromegaly were performed by Mann-Whitney rank sum test. A p value < 0.05 was considered to be significant.

	RESULTS

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Five of 10 patients with acromegaly had ODI greater than 10 h¹ with evident hypersomnolence. The five patients (Patients 1 through 5) were not obese, with BMI of less than 27 kg/m². Endoscopic evaluation of pharyngeal mechanics was successfully performed in nine patients with acromegaly although we could not obtain data from one patient owing to technical difficulty.

Pressure-area relationships of the velopharynx and oropharynx for each patient were satisfactorily fitted by the exponential function as exhibited in Figure 1 and Table 3. The narrowest site was the edge of the soft palate in the velopharyngeal airway and the base of the tongue in the oropharyngeal airway. P'close ranged from 6.4 to 6.1 cm H₂O at the velopharynx and from 6.4 to 4.9 cm H₂O at the oropharynx. Notably, five acromegalic patients with ODI greater than 10 h¹ had positive P'close at the oropharynx and all but one patient also had positive P'close at the velopharynx. Amax, K, and P'close at the oropharynx did not significantly differ from those of the velopharynx except constant B, which has no physiological significance.

View larger version (35K): [in this window] [in a new window]   Figure 1.   Static pressure-area relationships of passive pharynx are exhibited for all patients with acromegaly. Open and closed circles represent measured pressure-area data points of the velopharynx and oropharynx, respectively. Curves represent results of curve fitting analysis by an exponential function. VP = velopharynx, OP = oropharynx.

Results of the comparison of mechanical parameters between age-, BMI-, and ODI-matched SDB patients with and without acromegaly were presented in Table 2. Acromegalic patients with SDB had significantly higher P'close at the oropharynx than nonacromegalic patients with SDB.

	DISCUSSION

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This is the first detailed description of intrinsic mechanical properties of the passive pharynx in patients with active acromegaly. We found that a passive pharynx in acromegalic patients with a moderate degree of nocturnal hypoxemia was highly collapsible at the retroglossal as well as the retropalatal segment.

Methodological Considerations

Both neuromuscular and anatomic factors influence pharyngeal patency. Like ordinary sleep apnea, reduction of upper airway muscle activity at sleep onset appears to be an initial key event for the development of apnea in patients with acromegaly because disordered breathing does not usually occur during active contraction of upper airway muscles in the awake state. However, subsequent changes in upper airway muscle activity caused by shifts in sleep stages, along with a variety of mechanical and chemical reflexes acting on the upper airway, make estimation of contributory factors to pharyngeal patency difficult. As we previously reported, total paralysis produced by administration of muscular relaxant allowed separation of the neuromuscular from the anatomic factor (13). Although our method does not evaluate the role of the impaired neuromuscle factor in airway occlusion, and pharmacologically induced paralysis may not represent spontaneous apneic events during sleep in these patients, the method enables us to obtain static pressure-area relationship of the passive pharynx, which represents intrinsic mechanical properties of the pharynx.

In all our patients with acromegaly, disease activity is considered to be active owing to high IGF-1 levels, which appears to influence the severity of SDB in acromegaly. Either central or obstructive apnea/hypopneas during sleep causes episodic oxygen desaturations. According to Grunstein and coworkers, central sleep apnea is associated with increased ventilatory response to carbon dioxide and hypersecretion of growth hormone in patients with acromegaly, indicating the importance of respiratory control in the development of SDB in acromegaly (4, 17). Unfortunately, the nature of SDB was not clarified, and therefore the predominance of the type of SDB for each patient was not determined in this study because we did not perform standard polysomnographic recordings. Acromegalic patients with predominantly central sleep apnea, of which prevalence is reported to be 33% of acromegalic patients with SDB (4), possibly have less collapsible pharynx than those with predominantly obstructive apnea. Because nocturnal desaturations observed in this study were possibly caused by either central or obstructive events, our experimental design did not allow us to properly estimate the contribution of anatomic abnormalities to obstructive events during sleep in this group of patients.

Site of Upper Airway Obstruction in Acromegaly

Although upper airway obstruction is known to be a significant clinical manifestation in acromegaly since Chappel's first report (18), the etiology and site of upper airway obstruction are still controversial. Mezon and colleagues endoscopically observed posterior displacement of the enlarged tongue causing apnea during sleep in one case (10). Cadieux and colleagues, however, did not confirm Mezon's observation and described that lateral and posterior hypopharyngeal walls collapsed on inspiration and invaginated into the laryngeal vestibule during apnea in two acromegalic patients (11). More recently, endoscopic evaluation during sleep performed by Pelttari and coworkers revealed that upper airways are more collapsible at the level of the soft palate than at the base of the tongue in 11 treated acromegalic patients (12). A possible explanation for the controversial observations is the presence of uncontrolled upper airway muscle activities and airway pressure swing during breathing. Our results, obtained under control of upper airway muscle activities and the airway pressure, indicate that entire pharyngeal segments are highly collapsible in all five acromegalic patients with SDB. Because soft tissue swelling and hyperplasia of connective tissue are likely to occur in any part of the body in acromegaly, it is reasonable to find higher collapsibility along the pharyngeal airway.

Does the Etiology of SDB in Acromegaly Differ from That in Ordinary Sleep Apnea?

Unlike ordinary OSA, obesity does not appear to play a key role in the pathogenesis of SDB in acromegaly because our acromegalic patients as well as reported acromegalic patients with SDB were not significantly obese. Furthermore, our endoscopic evaluation of the pharynx clearly indicates that the passive mechanical properties of the pharynx in acromegalic patients with SDB are qualitatively different from age-, BMI-, and ODI-matched nonacromegalic patients with SDB. The former had significantly more collapsible tongue base than the latter, whereas no other mechanical parameters differed between the groups. These evidences strongly suggest a different etiology and importance of anatomic abnormalities at the base of the tongue for development of SDB in acromegaly. This is further supported by the fact that the severity of nocturnal hypoxemia appears to be associated with the collapsibility of the oropharyngeal airway in acromegalic patients, whereas the velopharyngeal collapsibility was reported to be a major determinant of the severity of nocturnal hypoxemia in nonacromegalic patients.

Another vital issue is that the frequency of SDB in acromegaly has been reported to decrease after surgical or pharmacological control of disease activity (8, 9, 19). Although this was mainly attributed to reduction of central apneic episodes (17, 19), reduction of soft tissue swelling after the treatment possibly leading to reduction of collapsibility of the pharynx may be an alternative mechanism. Bengtsson and coworkers estimated soft tissue swelling and cell proliferation leading to a 15% increase in extracellular water and a 10% increase in cell mass (20). Clearly, future studies should be directed toward assessing changes in pharyngeal collapsibility after control of disease activity.

In conclusion, the pharynx of acromegalic patients with SDB is highly collapsible at both tongue base and soft palate edges, and the etiology of SDB in acromegaly appears to differ from that of ordinary sleep apnea. The alteration of anatomic upper airway configuration during the disease process appears to play a significant role in the development of SDB in acromegaly although our results do not exclude the importance of central respiratory control deficiency.