Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome.

Obstructive Sleep Apnea (OSA) is considerably more common in men than women. Preliminary data suggest that androgens may play a role in the male predominance of apnea. Polycystic Ovary Syndrome (PCOS) is characterized by menstrual disturbances, androgen excess, and frequently obesity. These features suggest that women with PCOS may be at increased risk for OSA. To determine whether obese women with PCOS have an increased prevalence of sleep apnea compared with age and weight-matched reproductively normal women, we performed overnight polysomnography for determination of the apnea-hypopnea index (AHI) in 18 obese women with PCOS and age and weight-matched control women. Additional measurements included waist, hip, and neck circumferences, serum total testosterone, unbound testosterone, and DHEAS. Women with PCOS had a higher AHI than controls (22.5 +/- 6.0, vs. 6.7 +/- 1.0, P = 0.008). Women with PCOS were also more likely to suffer from symptomatic OSA syndrome (44.4% vs. 5.5%, P = 0.008). AHI correlated with waist-hip ratio (r = 0.51, P < 0.03), serum testosterone (r = 0.52, P < 0.03) and unbound testosterone (r = 0.50, P < 0.05) in women with PCOS. We conclude that obese women with PCOS are at increased risk of OSA when compared with matched reproductively normal women. Women with PCOS should be carefully questioned regarding symptoms of sleep apnea.

Reduced genioglossal activity with upper airway anesthesia in awake patients with OSA.

We examined whether topical upper airway anesthesia leads to a reduction in genioglossal (GG) electromyogram (EMG) in patients with obstructive sleep apnea (OSA). Airway mechanics were also evaluated. In 13 patients with OSA, we monitored GG EMG during tidal breathing and during the application of pulses of negative airway pressure (-10 to -12 cmH(2)O). Airflow resistance and airway collapsibility were determined. All measurements were performed with and without topical anesthesia (lidocaine). Anesthesia led to a significant fall in the peak GG EMG response to negative pressure from 36.1 +/- 4.7 to 24.8 +/- 5.3% (SE) of maximum (P < 0.01). This was associated with a fall in phasic and tonic EMG during tidal breathing (phasic from 24.4 +/- 4.1 to 16.4 +/- 3.4% of maximum and tonic from 10.9 +/- 1.6 to 8.0 +/- 1.3% of maximum, P < 0.01). A significant rise in pharyngeal airflow resistance was also observed. Our results demonstrate that topical receptor mechanisms in the nasopharynx importantly influence dilator muscle activity and are likely important in driving the augmented dilator muscle activity seen in the apnea patient.

Upper airway muscle responsiveness to rising PCO(2) during NREM sleep.

Although pharyngeal muscles respond robustly to increasing PCO(2) during wakefulness, the effect of hypercapnia on upper airway muscle activation during sleep has not been carefully assessed. This may be important, because it has been hypothesized that CO(2)-driven muscle activation may importantly stabilize the upper airway during stages 3 and 4 sleep. To test this hypothesis, we measured ventilation, airway resistance, genioglossus (GG) and tensor palatini (TP) electromyogram (EMG), plus end-tidal PCO(2) (PET(CO(2))) in 18 subjects during wakefulness, stage 2, and slow-wave sleep (SWS). Responses of ventilation and muscle EMG to administered CO(2) (PET(CO(2)) = 6 Torr above the eupneic level) were also assessed during SWS (n = 9) or stage 2 sleep (n = 7). PET(CO(2)) increased spontaneously by 0.8 +/- 0.1 Torr from stage 2 to SWS (from 43.3 +/- 0.6 to 44.1 +/- 0.5 Torr, P < 0.05), with no significant change in GG or TP EMG. Despite a significant increase in minute ventilation with induced hypercapnia (from 8.3 +/- 0.1 to 11.9 +/- 0.3 l/min in stage 2 and 8.6 +/- 0.4 to 12.7 +/- 0.4 l/min in SWS, P < 0.05 for both), there was no significant change in the GG or TP EMG. These data indicate that supraphysiological levels of PET(CO(2)) (50.4 +/- 1.6 Torr in stage 2, and 50.4 +/- 0.9 Torr in SWS) are not a major independent stimulus to pharyngeal dilator muscle activation during either SWS or stage 2 sleep. Thus hypercapnia-induced pharyngeal dilator muscle activation alone is unlikely to explain the paucity of sleep-disordered breathing events during SWS.

Sleep. 2: pathophysiology of obstructive sleep apnoea/hypopnoea syndrome.

The pathogenesis of airway obstruction in patients with obstructive sleep apnoea/hypopnoea syndrome is reviewed. The primary defect is probably an anatomically small or collapsible pharyngeal airway, in combination with a sleep induced fall in upper airway muscle activity.

Local mechanisms drive genioglossus activation in obstructive sleep apnea.

Individuals with obstructive sleep apnea (OSA) require increased pharyngeal muscle dilator activation during wakefulness to maintain upper airway patency. Negative pressure is one potential stimulus for this neuromuscular compensation. Individuals with OSA who have previously undergone tracheostomy provide an opportunity to study upper airway physiology in both the presence and absence of upper airway respiratory stimuli. If negative pressure (or another local airway stimulus) were important in driving pharyngeal dilator muscle activation, one would predict that during nasal breathing, the pharynx of a tracheostomized patient would be exposed to negative pressure, and that high levels of muscle activation would therefore be measured. Conversely, during breathing by the patient through the tracheal stoma, one would expect low levels of muscle activation in the absence of local stimuli. We measured a number of respiratory variables, including genioglossus activation under both nasal and tracheal stomal breathing conditions, in five patients. In all five patients there was a significant and substantial decrease in both peak phasic (100 +/- 0 to 53.4 +/- 9.2 arbitrary units [mean +/- SEM], p < 0.01) and tonic genioglossus activation (36.3 +/- 5.3 to 20.7 +/- 3.9 arbitrary units, p < 0.05) during stomal breathing as compared with nasal breathing. We conclude that local upper airway respiratory stimuli, possibly negative pressure, are important in mediating the increased pharyngeal dilator muscle activation seen in sleep apnea patients during wakefulness.

Genioglossal inspiratory activation: central respiratory vs mechanoreceptive influences.

Upper airway dilator muscles are phasically activated during respiration. We assessed the interaction between central respiratory drive and local (mechanoreceptive) influences upon genioglossal (GG) activity throughout inspiration. GG(EMG) and airway mechanics were measured in 16 awake subjects during baseline spontaneous breathing, increased central respiratory drive (inspiratory resistive loading; IRL), and decreased respiratory drive (hypocapnic negative pressure ventilation), both prior to and following dense upper airway topical anesthesia. Negative epiglottic pressure (P(epi)) was significantly correlated with GG(EMG) across inspiration (i.e. within breaths). Both passive ventilation and IRL led to significant decreases in the sensitivity of the relationship between GG(EMG) and P(epi) (slope GG(EMG) vs P(epi)), but yielded no change in the relationship (correlation) between GG(EMG) and P(epi). During negative pressure ventilation, pharyngeal resistance increased modestly, but significantly. Anesthesia in all conditions led to decrements in phasic GG(EMG), increases in pharyngeal resistance, and decrease in the relationship between P(epi) and GG(EMG). We conclude that both central output to the GG and local reflex mediated activation are important in maintaining upper airway patency.

Genioglossal activation in patients with obstructive sleep apnea versus control subjects. Mechanisms of muscle control.

Pharyngeal dilator muscle activation (GGEMG) during wakefulness is greater in patients with obstructive sleep apnea (OSA) than in healthy control subjects, representing a neuromuscular compensatory mechanism for a more collapsible airway. As previous work from our laboratory has demonstrated a close relationship between GGEMG and epiglottic pressure, we examined the relationship between genioglossal activity and epiglottic pressure in patients with apnea and in control subjects across a wide range of epiglottic pressures during basal breathing, negative-pressure (iron-lung) ventilation, heliox breathing, and inspiratory resistive loading. GGEMG was greater in the patients with apnea under all conditions (p < 0.05 for all comparisons), including tonic, phasic, and peak phasic GGEMG. In addition, patients with apnea generated a greater peak epiglottic pressure on a breath-by-breath basis. Although the relationship between GGEMG and epiglottic negative pressure was tight across all conditions in both groups (all R values > = 0.69), there were no significant differences in the slope of this relationship between the two groups (all p values > 0.30) under any condition. Thus, the increased GGEMG seen in the patient with apnea during wakefulness appears to be a product of an increased tonic activation of the muscle, combined with increased negative-pressure generation during inspiration.

Genioglossal but not palatal muscle activity relates closely to pharyngeal pressure.

The stimuli controlling pharyngeal dilator muscles are poorly defined. Local mechanoreceptors are a leading possibility. To address this, we assessed the relationship between two dilator muscle electromyograms (EMGs, i.e., genioglossus [GG-an inspiratory phasic muscle], tensor palatini [TP-a tonically active muscle]) and potential stimuli (i.e., epiglottic pressure [Pepi], airflow [V], and pharyngeal resistance [Rpha]). Fifteen normal subjects were studied, during wakefulness and stable non-rapid eye movement (NREM) sleep. The GGEMG and TPEMG were assessed during basal breathing and during inspiratory resistive loading (four loads, done in triplicate), while quantifying Pepi and choanal pressures (Pcho, Millar catheters) plus V. There was a strong correlation between Pepi and GGEMG during wakefulness in most subjects (9 of 15 had absolute R > 0.7 [p < 0.05], group mean R = -0.62, p < 0.05). These correlations were less robust during NREM sleep (8 of 15 absolute R > 0.6 [p < 0.05], group mean R = -0.39, ns). The slope of the Pepi versus GGEMG relationship was greater during wakefulness than sleep (-0.67 versus -0.39% max/ cm H(2)O, p < 0.05). No significant correlations were observed between TPEMG and any of the measured potential stimuli. We conclude that intrapharyngeal pressure may modulate genioglossus activity during wakefulness, with a fall in muscle responsiveness during sleep. The activity of the TP was not clearly influenced by any measured local stimulus either awake or asleep.

D-dimers in the diagnosis of pulmonary embolism.

The aim of this study was to determine if the absence of circulating D-dimers, as determined by latex agglutination assays, can correctly exclude the presence of pulmonary embolism using pulmonary angiography as the diagnostic endpoint. Blood samples were obtained prospectively at the time of angiography for suspicion of acute pulmonary embolism. Plasma was assayed for D-dimer by five different latex agglutination assays. Angiographic evidence of pulmonary emboli was found in 34% (35/ 103) of patients. The latex agglutination assays had sensitivities of 97 to 100% and specificities of 19 to 29%. The negative predictive value was 94 to 100%. However, a negative D-dimer was rare in patients with recent surgery, malignancy, or total bilirubin > 34 micromol/L (> 2 mg/dl). In 31 patients suspected of pulmonary emboli but without these confounding factors, the five D-dimer assays were negative in 46 to 55% of patients with normal pulmonary angiograms. The negative predictive value in these patients was 100% by all five latex agglutination assays tested. The latex agglutination assays for D-dimer, when the pulmonary angiogram is used as the diagnostic endpoint and in the absence of recent surgery, malignancy, or liver disease, appears to be a clinically useful test in the diagnosis of acute pulmonary embolism.