Trazodone increases arousal threshold in obstructive sleep apnoea.

A low arousal threshold is believed to predispose to breathing instability during sleep. The present authors hypothesised that trazodone, a nonmyorelaxant sleep-promoting agent, would increase the effort-related arousal threshold in obstructive sleep apnoea (OSA) patients. In total, nine OSA patients, mean+/-sd age 49+/-9 yrs, apnoea/hypopnoea index 52+/-32 events.h(-1), were studied on 2 nights, one with trazodone at 100 mg and one with a placebo, in a double blind randomised fashion. While receiving continuous positive airway pressure (CPAP), repeated arousals were induced: 1) by increasing inspired CO(2) and 2) by stepwise decreases in CPAP level. Respiratory effort was measured with an oesophageal balloon. End-tidal CO(2 )tension (P(ET,CO(2))) was monitored with a nasal catheter. During trazodone nights, compared with placebo nights, the arousals occurred at a higher P(ET,CO(2)) level (mean+/-sd 7.30+/-0.57 versus 6.62+/-0.64 kPa (54.9+/-4.3 versus 49.8+/-4.8 mmHg), respectively). When arousals were triggered by increasing inspired CO(2) level, the maximal oesophageal pressure swing was greater (19.4+/-4.0 versus 13.1+/-4.9 cm H(2)O) and the oesophageal pressure nadir before the arousals was lower (-5.1+/-4.7 versus -0.38+/-4.2 cm H(2)O) with trazodone. When arousals were induced by stepwise CPAP drops, the maximal oesophageal pressure swings before the arousals did not differ. Trazodone at 100 mg increased the effort-related arousal threshold in response to hypercapnia in obstructive sleep apnoea patients and allowed them to tolerate higher CO(2) levels.

Effect of increased lung volume on sleep disordered breathing in patients with sleep apnoea.

BACKGROUND: Previous studies have shown that changes in lung volume influence upper airway size and resistance, particularly in patients with obstructive sleep apnoea (OSA), and that continuous positive airway pressure (CPAP) requirements decrease when the lung volume is increased. We sought to determine the effect of a constant lung volume increase on sleep disordered breathing during non-REM sleep. METHODS: Twelve subjects with OSA were studied during non-REM sleep in a rigid head-out shell equipped with a positive/negative pressure attachment for manipulation of extrathoracic pressure. The increase in lung volume due to CPAP (at a therapeutic level) was determined with four magnetometer coils placed on the chest wall and abdomen. CPAP was then stopped and the subjects were studied for 1 hour in three conditions (in random order): (1) no treatment (baseline); (2) at "CPAP lung volume", with the increased lung volume being reproduced by negative extrathoracic pressure alone (lung volume 1, LV1); and (3) 500 ml above the CPAP lung volume(lung volume 2, LV2). RESULTS: The mean (SE) apnoea/hypopnoea index (AHI) for baseline, LV1, and LV2, respectively, was 62.3 (10.2), 37.2 (5.0), and 31.2 (6.7) events per hour (p = 0.009); the 3% oxygen desaturation index was 43.0 (10.1), 16.1 (5.4), and 12.3 (5.3) events per hour (p = 0.002); and the mean oxygen saturation was 95.4 (0.3)%, 96.0 (0.2)%, 96.3 (0.3)%, respectively (p = 0.001). CONCLUSION: An increase in lung volume causes a substantial decrease in sleep disordered breathing in patients with OSA during non-REM sleep.

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.

Heart rate chaos in obstructive sleep apnea in children.

Obstructive sleep apnea syndrome (OSAS) in children is associated with a bradytachyarrhythmia during an obstructive event. Polysomnographic recordings were obtained from 15 children; 9 had OSAS (apnea/hypopnea index = 13.6 +/- 8.2/hr, mean +/- SD) and 6 normal controls. Heart rate variability was analyzed for the presence of chaotic dynamics. Using a 5-minute sliding window, chaos was detected using numerical titration technique. In both groups, REM had a higher chaotic intensity than NREM sleep (p < 0.05). Furthermore, chaos was significantly increased during periods with apneic events compared to stable breathing. These data indicate that sleep state and disordered breathing are important determinants of the autonomic control of heart rate chaos in children.

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 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.

Upper-airway collapsibility: measurements and sleep effects.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by repetitive pharyngeal collapse during sleep. Several techniques have been proposed to assess the collapsibility of the upper airway in awake humans, but sleep-wake comparisons have rarely been attempted and there are few studies comparing OSA patients to control subjects. We sought to compare two collapsibility measurement techniques between normal and apneic subjects, and between wakefulness and sleep. DESIGN: We conducted three studies. First, we examined whether collapsibility assessed by negative pressure pulses (NPPs) during wakefulness reflected values during sleep in 21 normal subjects. Second, we determined in these normal subjects whether collapsibility during sleep assessed by NPPs was predictive of collapsibility measured by inspiratory resistive loading (IRL). Finally, we compared upper-airway collapsibility between apnea patients (n = 22) and normal volunteers (n = 38) during wakefulness by NPPs. SETTING: Clinical and research laboratories at the Brigham and Women's Hospital. PARTICIPANTS: Two populations of normal subjects (n = 21 and n = 38) and OSA patients (n = 22). MEASUREMENTS AND RESULTS: Collapsibility during wakefulness, as measured by NPPs, correlated significantly with collapsibility during sleep (r = 0.62; p = 0.003). There was also a significant correlation between the two measures of collapsibility (IRL and NPP) during sleep (r = 0.53; p = 0.04). Both measures revealed a significant increase in pharyngeal collapsibility during sleep as compared to wakefulness. Finally, apnea patients had significantly greater pharyngeal collapsibility than control subjects during wakefulness (p = 0.017). CONCLUSIONS: These data suggest that upper-airway collapsibility measured during wakefulness does provide useful physiologic information about pharyngeal mechanics during sleep and demonstrates clear differences between individuals with and without sleep apnea.

Phasic mechanoreceptor stimuli can induce phasic activation of upper airway muscles in humans.

1. Upper airway dilator muscles are phasically activated throughout breathing by respiratory pattern generator neurons. Studies have shown that non-physiological upper airway mechanoreceptive stimuli (e.g. rapidly imposed pulses of negative pressure) also activate these muscles. Such reflexes may become activated during conditions that alter airway resistance in order to stabilise airway patency. 2. To determine the contribution of ongoing mechanoreceptive reflexes to phasic activity of airway dilators, we assessed genioglossal electromyogram (GG EMG: rectified with moving time average of 100 ms) during slow (physiological) oscillations in negative pressure generated spontaneously and passively (negative pressure ventilator). 3. Nineteen healthy adults were studied while awake, during passive mechanical ventilation across normal physiological ranges of breathing rates (13-19 breaths min-1) and volumes (0.5-1.0 l) and during spontaneous breathing across the physiological range of end-tidal carbon dioxide (PET,CO2; 32-45 mmHg). 4. Within-breath phasic changes in airway mechanoreceptor stimuli (negative pressure or flow) were highly correlated with within-breath phasic genioglossal activation, probably representing a robust mechanoreceptive reflex. These reflex relationships were largely unchanged by alterations in central drive to respiratory pump muscles or the rate of mechanical ventilation within the ranges studied. A multivariate model revealed that tonic GG EMG, PET,CO2 and breath duration provided no significant independent information in the prediction of inspiratory peak GG EMG beyond that provided by epiglottic pressure, which alone explained 93 % of the variation in peak GG EMG across all conditions. The overall relationship was: Peak GG EMG = 79.7 - (11.3 X Peak epiglottic pressure), where GG EMG is measured as percentage of baseline, and epiglottic pressure is in cmH2O. 5. These data provide strong evidence that upper airway dilator muscles can be activated throughout inspiration via ongoing mechanoreceptor reflexes. Such a feedback mechanism is likely to be active on a within-breath basis to protect upper airway patency in awake humans. This mechanism could mediate the increased genioglossal activity observed in patients with obstructive sleep apnoea (i.e. reflex compensation for an anatomically smaller airway).

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.

Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender.

The male predominance in obstructive sleep apnea (OSA) is currently poorly understood although differences in pharyngeal airway anatomy and physiology have been proposed. As the response to inspiratory resistive loading (IRL) provides important information on both airway collapsibility (mechanics) and ventilatory control, we compared this respiratory response in eight normal women and eight age and body mass index (BMI)-matched men, during stable nonrapid eye movement (NREM) sleep. Upper airway mechanics, ventilation, plus activation of two dilator muscles (genioglossus [GG] and tensor palatini [TP]) were monitored during basal breathing (BL), followed by four sequentially applied loads (5, 10, 15, 25 cm H(2)O/L/s) for three breaths each. Men developed more severe hypopnea in response to identical applied external loads than did women. At a resistance of 25 cm H(2)O/L/s, VT decreased by 26 +/- 1% in women compared with 44 +/- 1% in men (differences between sexes p < 0.05). Pharyngeal resistance (Rpha) in response to IRL increased significantly more in men than women (37.3 +/- 11.2 cm H(2)O/L/s in men at maximal load, compared with an increase of 6.6 +/- 3.9 cm H(2)O/L/s in women, p < 0.05). Men and women had near identical minute ventilation responses to total load (applied extrinsic plus measured intrinsic), implying no differences in central drive or load response. There were no significant increases in GG or TP activation in response to IRL in either sex. We conclude that normal men are more vulnerable to load-induced hypoventilation than women, due to increased upper airway collapse, which could not be explained by differences in dilator muscle activation. This implies a fundamental difference in the upper airway anatomy and/or tissue characteristics between the two sexes.

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.

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.

Influence of chemoreceptor stimuli on genioglossal response to negative pressure in humans.

Genioglossal muscle (GG) activity is modulated by both chemoreceptive and mechanoreceptive reflexes that help stabilize airway patency. We assessed the effects of blood gas changes, within the range encountered during mild obstructive apnea-arousal cycles, on GG activity and the GG reflex to upper airway negative pressure. Eighteen healthy adults were studied while awake under 5 conditions: (1) baseline (PET(CO(2)) = 40 mm Hg, Sa(O(2)) = 99%); (2) hypercapnia (PET(CO(2)) = 45 mm Hg); (3) hypocapnia (PET(CO(2)) = 35 mm Hg, induced via hyperventilation with an iron lung ventilator); (4) hypoxia (Sa(O(2)) = 87%); and (5) hypercapnia plus hypoxia (PET(CO(2)) = 45 mm Hg, Sa(O(2)) = 87%). Measurements included airflow, choanal and epiglottic pressures (Pchoa and Pepi), upper airway resistance, phasic and tonic GG EMG, and the GG reflex to negative pressure (Pchoa = -12.5 cm H(2)O). Ventilation increased from a baseline of 10.7 up to 22.7 L. min(-1) under conditions of altered blood gases. Peak inspiratory phasic GG EMG increased from 6. 5 to 11.1% of maximal contraction but there were no significant changes in either tonic GG EMG (range, 4.3 to 5.8% of maximum) or magnitude of the GG reflex (range, 4.1 to 5.5% of maximum). Among conditions there was a high correlation between upper airway pressures and peak phasic GG EMG (Pchoa, r = 0.97, p < 0.01; Pepi, r = 0.87; p = 0.06). We conclude that in this range of blood gases: (1) the GG reflex to negative pressure is unchanged; (2) slow airway pressure changes throughout inspiration, generated either actively or passively, influence GG EMG activity; and (3) mechanoreceptive control of GG EMG can fully explain all changes in GG activity, suggesting that chemoreceptive inputs to GG are minimal, or are not simply summated with mechanoreceptor inputs.

The influence of a transmucosal cholinergic agonist on pharyngeal muscle activity.

STUDY OBJECTIVE: To assess the effect of high local oral nicotine administration on the upper airway (UA) of normal males during wakefulness. DESIGN: Nonrandomized study. SETTING: Brigham & Women's Hospital General Clinical Research Center. PARTICIPANTS: Two groups of 13 and 12 normal male subjects were evaluated. INTERVENTIONS: A "Fast acting" or "Intermediate acting" 2 mg transmucosal nicotine patch was attached to an upper molar tooth of study participants during wakefulness. MEASUREMENTS: All data were collected prior to, and at several time points after, patch placement. Data measured included serum nicotine levels, genioglossal EMG, and pharyngeal resistance during basal breathing as well as the UA muscle response and UA collapsibility during negative UA pressure pulses. RESULTS: None of the variables measured showed a statistically significant change with either nicotine patch despite a significant rise (p<0.05) in nicotine serum levels post patch placement in both groups. In several subjects, muscle activity and responsiveness to negative pressure increased after application of both patches and returned to near baseline levels at the last time point measured, a response consistent with the time course of nicotine release in both patches. CONCLUSIONS: Oral nicotine administration failed to consistently increase GG muscle activation which may be a problem of local bioavailability of nicotine in the muscle.

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.

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.

Effect of wake-sleep transitions and rapid eye movement sleep on pharyngeal muscle response to negative pressure in humans.

1. Genioglossus (GG) activation in response to upper airway negative pressure may be an important mechanism in the maintenance of airway patency. This reflex occurs during wakefulness but is diminished during stable non-rapid eye movement (NREM) sleep. Since obstructive events occur more commonly at wake-sleep transitions and during rapid eye movement (REM) sleep than during stable NREM sleep, we assessed the GG reflex during these two vulnerable states. 2. Seventeen healthy adults were studied throughout one evening and overnight. Electroencephalograms (EEGs), electro-oculograms (EOGs), submental electromyogram (EMG), GG EMG (intramuscular electrodes), and choanal plus epiglottic pressures were recorded. The GG reflex response to pulses of -8 cmH2O choanal pressure applied via nose mask during early inspiration was quantified repeatedly during relaxed wakefulness, within five breaths of wake-sleep transition (EEG alpha-theta transition) and during REM sleep. Only trials without EEG arousal were analysed, resulting in data from 14 subjects during sleep onset and 10 subjects during REM sleep (overall, 174-491 trials per state). 3. During wakefulness there was brisk GG reflex activation in response to negative pressure (amplitude: +78.5 +/- 28.3 % baseline (mean +/- s.e.m.); latency to maximal response: 177 +/- 16 ms). 4. At sleep onset, although there was marked variability among individuals, there was no significant reduction in the magnitude of the GG reflex for the group as a whole (amplitude: +33.2 +/- 8.2 % baseline; latency: 159 +/- 15 ms). 5. In contrast, during REM sleep there was a reduction of GG reflex (amplitude: -12.6 +/- 8.3 % baseline (P = 0.017 vs. awake); latency: 160 +/- 10 ms (n.s. vs. awake)) and greater airway collapsibility during the applied pressures (P = 0.043 vs. awake). 6. We conclude that there was no systematic reduction in the GG reflex to negative pressure at sleep onset. Nonetheless, it remains possible that sleep-deprived normal subjects and patients with sleep apnoea could react differently. 7. The apparent inhibition of the GG reflex during REM sleep may help explain why the upper airway is vulnerable to collapse during this state.