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An important mechanism controlling genioglossus (GG) muscle activity is the reflex response to negative airway pressure. We hypothesize that this reflex response may be lost during sleep and believe that this loss may be important in the pathogenesis of airway collapse during sleep. Thus, we determined the effect of non-rapid eye movement (NREM) sleep on the GG electromyogram (EMG) response to brief (0.2 to 0.6 s) episodes of negative pressure generation (NPG) in the upper airway of six normal subjects. Up to 100 NPGs (mean 58 +/- 12) were recorded both awake and during stable NREM sleep. During wakefulness, the change in GG moving time average EMG from basal to peak levels (during NPG) was 17.1 +/- 2.5 au (a 154 +/- 22% increase above basal levels). This response was markedly reduced during NREM sleep (2.7 +/- 1.2 au; p < 0.01). The latency of the GG EMG response was 53.8 +/- 11.5 ms during wakefulness (n = 6), but much longer during sleep (132.7 +/- 24.5 ms; n = 3; p < 0.03). We conclude that in normal subjects (1) the GG muscle responds to negative airway pressure by reflex activation during wakefulness, and (2) this reflex activation is reduced or lost during NREM sleep. We speculate that loss of this mechanism during sleep may contribute to pharyngeal collapse in obstructive apnea patients.

To determine the effect of non-REM (NREM) sleep on inspiratory muscle electromyographic (EMG) activity in asthmatic patients and the subsequent effect of such changes on FRC, 12 asthmatic patients with nocturnal worsening were monitored overnight in a horizontal volume-displacement body plethysmograph. During studies FRC was monitored using the single inspiratory occlusion technique, whereas EMG activities of the diaphragm (DI), intercostal (IC), and sternocleidomastoid (SCM) muscles were monitored using surface electrodes. FRC decreased progressively, from 3.63 +/- 0.27 L while awake prior to "lights out" to 3.15 +/- 0.27 L after 60 min of NREM sleep (p < 0.005). With awakening at the end of the study FRC increased to 4.69 +/- 0.48 L (p < 0.01). Onset of NREM sleep was also associated with significant (p < 0.05) reductions in EMG tonic activities of all three inspiratory muscles. These levels of tonic activity returned and were further augmented (p < 0.001) with awakening at the conclusion of the study. Linear relationships were demonstrated between sleep-state dependent changes in FRC and EMG tonic activity for each of the three inspiratory muscles (r = 0.98, 0.93, and 0.97 for DI, IC, and SCM, respectively, p < 0.01). NREM sleep did not significantly alter mean inspiratory phasic activities of these muscles, although there was considerable heterogeneity between individual subjects in the effects of NREM sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Nocturnal worsening occurs commonly in the asthmatic patient population and contributes substantially to the morbidity and even mortality of asthma. However, no physiologic process has yet been identified as the major contributor to this pattern. Sleep is typically associated with both the supine posture and substantial decrements in lung volume, and both have been proposed to have a role in the pattern of nocturnal worsening. To assess the effects of posture and sleep-associated reductions in functional residual capacity on pulmonary function, eight asthmatic patients were first monitored overnight in a horizontal volume-displacement body plethysmograph to determine mean FRC during sleep for each subject. We then compared, during wakefulness, the effects on FEV1 and methacholine responsiveness from chest wall and abdomen strapping (to maintain FRC at mean sleep levels) for 6 h in the supine and upright postures. FEV1 was significantly decreased after strapping in the supine posture (2.54 +/- 0.36 versus 3.38 +/- 0.29 L on control day, p = 0.0001) but was not affected by strapping in the upright posture (3.07 +/- 0.30 versus 3.34 +/- 0.31 L on control day, not significant, NS). Bronchial responsiveness to methacholine was not altered after strapping in either posture. These observations suggest that the supine posture, in conjunction with the reduction in lung volume associated with sleep, may contribute to the nocturnal worsening of asthma.

Arousal from sleep in response to asphyxia can be a lifesaving event. However, the mechanisms responsible for this important arousal response are uncertain. A unifying hypothesis is that arousal results from the increased respiratory effort that occurs as a result of ventilatory stimulation. If this is true, the magnitude of this effort during the breaths immediately preceding arousal from sleep should be similar regardless of the stimulus. Therefore, the negative inspiratory pleural pressure during the breaths preceding arousal would be similar, whether stimulated by added inspiratory resistive load, hypoxia, or hypercapnia. To test this hypothesis, we studied eight young, healthy men during full-night sleep studies. We measured their electroencephalography (EEG), electromyography (EMG), electrooculography (EOG), inspired ventilation (VI), end tidal PCO2 (PETCO2), O2 saturation, and esophageal pressure (esophageal balloon) while inducing arousal from non-REM sleep using (1) a 30-cm H2O/L/s added resistive load, (2) progressive hypoxia, and (3) progressive hyperoxic hypercapnia. All subjects were eventually aroused following the addition of the 30-cm H2O/L/s added load and during progressive hypercapnia. However, only six of the eight men were aroused when the O2 saturation was reduced to a minimum of 70%. For each stimulus, arousal occurred at very different levels of ventilation and arterial chemistry (SaO2 and CO2). However, ventilatory effort for each subject was similar at the point of arousal regardless of the stimulus. The peak-negative esophageal pressure for the single inspiration preceding arousal (for the six subjects arousing with all three stimuli) was 16.8 +/- 1.4 cm H2O for added resistive load, 15.0 +/- 2.4 cm H2O for hypoxia, and 14.7 +/- 2.1 cm H2O for hypercapnia. We conclude that increasing ventilatory effort may be the stimulus to arousal from sleep independent of the source of this rising drive to breathe.

Inability to breathe through the nose is an increasingly recognized cause of disordered breathing during sleep. To test the hypothesis that this respiratory dysrhythmia could result from loss of neuronal input to respiration from receptors located in the nose, we anesthetized the nasal passages of 10 normal men during sleep. Each subject spent 4 consecutive nights in the sleep laboratory while sleep stages, breathing patterns, respiratory effort, and arterial oxygen saturation were monitored. Night 1 was for acclimatization with Nights 3 and 4 being randomized to nasal spraying with either 4% lidocaine or placebo. On the lidocaine and placebo nights (Nights 3 and 4) the nasal passages were also sprayed with a decongestant to prevent increased nasal air-flow resistance resulting from mucosal swelling. To control for the possible effects of this decongestant, an additional night (Night 2) was included during which the nasal passages were sprayed with room air. Parallel studies conducted during wakefulness demonstrated low nasal resistance during the lidocaine-decongestant regimen. Because of the short duration of anesthesia with lidocaine, spraying was done at lights out and 2.5 and 5 h later. On the placebo night (decongestant plus saline) there were 6.4 +/- 1.8 (SEM) disordered breathing events (apneas plus hypopneas) per subject, whereas with lidocaine (plus decongestant) this increased fourfold to 25.8 +/- 7.8 events per subject (p less than 0.05). The majority of the disordered breathing events were apneas and were fairly evenly distributed between central and obstructive events. The magnitude of these changes is similar to that previously reported with complete nasal obstruction. These results suggest that nasal receptors sensitive to air flow may be important in maintaining breathing rhythmicity during sleep.

That viral encephalitis can produce daytime hypoventilation is well appreciated, but an association of this infection with the development of a prolonged disturbance of breathing during sleep once the ventilatory disorder during wakefulness has resolved, has not been reported. We describe a young male who required assisted mechanical ventilation in association with western equine encephalitis. Normal waking ventilation returned over 3 to 4 wk, but frequent apneas and severe hypoventilation persisted during sleep with a near absence of waking ventilatory response to chemical stimuli. Over 3 months there was considerable improvement in breathing during sleep associated with an increase in both hypoxic and hypercapnic ventilatory responsiveness.

Apnea during sleep has been associated with both increased pharyngeal resistance and nasal obstruction. Alcohol can worsen obstructive sleep apnea, but its influence on pharyngeal resistance and nasal patency has not been evaluated. Accordingly, we determined the effects of alcohol on pharyngeal and nasal resistances in 11 normal awake subjects on 2 separate days. Baseline pharyngeal resistance prior to placebo and alcohol was not significantly different. After placebo, pharyngeal resistance did not change significantly. However, after alcohol, pharyngeal resistance increased from 1.9 +/- 0.5 (SEM) to 3.3 +/- 0.8 cm H2O/L/s at 45 min (p less than 0.05) and returned to near baseline level by 90 min. Baseline nasal resistance varied considerably within subjects on the 2 days, but the mean values for baseline nasal resistance on alcohol and placebo days were not significantly different. Nasal resistance did not change after placebo, but after alcohol, nasal resistance increased from 2.4 +/- 0.9 at baseline to 3.7 +/- 0.8 at 45 min (NS) and to 4.3 +/- 1.2 cm H2O/L/s at 90 min (p less than 0.05). We conclude that a decrease in pharyngeal airway size and an increase in nasal resistance may account for alcohol's ability to worsen obstructive sleep apnea.

During rapid eye movement (REM) sleep, hypoxia and hypercapnia occur in conjunction with hypoventilation. Although the hypoxic ventilatory response has previously been shown to be reduced in REM sleep, the hypercapnic ventilatory response (HCVR) has not been studied during REM sleep in adult humans. We therefore measured the ventilatory response to hypercapnia in 12 sleeping adults using a modified rebreathing method. The HCVR was significantly reduced in all stages of sleep compared with that during wakefulness (1.60 +/- 0.19 SEM L/min/mmHg CO2), falling to less than half the waking HCVR during non-REM sleep (0.75 +/- 0.08 L/min/mmHg CO2), with a further significant drop during REM sleep when HCVR was less than a third of that during wakefulness (0.45 +/- 0.10 L/min/mmHg CO2). The decreased ventilatory responses to hypercapnia and hypoxia in REM sleep help explain REM-related hypoxemic episodes.

Sleep deprivation is common in acutely ill patients because of their underlying disease and can be compounded by aggressive medical care. While sleep deprivation has been shown to produce a number of psychological and physiologic events, the effects on respiration have been minimally evaluated. We therefore studied resting ventilation and ventilatory responses to hypoxia and hypercapnia before and after 24 h of sleeplessness in 13 healthy men. Hypoxic ventilatory responses (HVR) were measured during progressive isocapnic hypoxia, and hypercapnic ventilatory responses (HCVR) were measured using a rebreathing technique. Measures of resting ventilation, i.e., minute ventilation, tidal volume, arterial oxygen saturation, and end-tidal gas concentrations, did not change with short-term sleep deprivation. Both HVR and HCVR, however, decreased significantly after a single night without sleep. The mean hypoxic response decreased 29% from a slope of 1.20 +/- 0.22 (SEM) to 0.85 +/- 0.15 L/min/% saturation (p less than 0.02), and the slope of the HCVR decreased 24% from 2.07 +/- 0.17 to 1.57 +/- 0.15 L/min/mmHg PCO2 (p less than 0.01). These data indicate that ventilatory chemosensitivity may be substantially attenuated by even short-term sleep deprivation. This absence of sleep could therefore contribute to hypoventilation in acutely ill patients.

Although anatomic and physiologic abnormalities of the upper airway are thought to be important in the pathogenesis of obstructive sleep apnea (OSA), the relative contributions of these factors have not been elucidated. We therefore measured pharyngeal cross-sectional area (PCSA) and pharyngeal air-flow resistance (Rp) in 12 overweight men with severe symptomatic OSA (mean apnea plus hypopnea index [AHI], 66.9 +/- 6.0 events per hour) and in 17 age- and weight-matched control subjects without spontaneous complaints of OSA symptoms (mean AHI, 4.9 +/- 1.6 events per hour). During wakefulness, PCSA was assessed during breath cessation at FRC by computed tomography (CT) and Rp by measuring inspiratory air-flow resistance between the choanae and epiglottis. No measure of PCSA differed significantly between patients and control subjects, and only 1 measure of PCSA, minimal pharyngeal area, correlated with AHI in all subjects (r = -0.38, p less than 0.05). In contrast, Rp was significantly higher (p less than 0.05) in patients (6.9 +/- 1.0 cm H2O/L/s) than in all control subjects (4.2 +/- 0.5 cm H2O/L/s) and correlated significantly with AHI (r = 0.53, p less than 0.01). We conclude that increased inspiratory resistance to air flow in the naso-oropharynx is present during wakefulness in overweight men with OSA, when compared with matched control subjects without symptomatic OSA, and is associated with disordered breathing during sleep. This occurs even though computed tomography is unable to demonstrate that pharyngeal size during wakefulness at FRC is significantly different between patients and control subjects. These observations suggest that the ability to dilate the pharynx during inspiration may be defective in patients with OSA.

Nasal obstruction has been associated with apneic episodes during sleep. However, the normal distribution of nasal and oral air flow while asleep has not been investigated. To determine the normal route of ventilation during sleep, we studied 7 healthy men and 7 healthy women using a sealed face mask that mechanically separated nasal and oral air flow. Standard sleep staging techniques were employed. The subjects slept 297 +/- 29 (SEM) min, with a mean of 197 +/- 15 min of ventilation recorded. Ventilation was decreased during sleep as has been previously demonstrated. However, during sleep, we found that men breathed a greater percentage of total ventilation through the mouth (29.0 +/- 8.2%) than did women (5.0 +/- 1.0%, p less than 0.02). The same trend applied during wakefulness but did not reach significance (p = 0.06). Although none was symptomatic, 4 subjects, all men, had more than 3 apneas per hour. These 4 men had a greater percentage of mouth ventilation (37.3 +/- 19.0%) than did the other 10 subjects with few or no apneas (8.1 +/- 2.7%, p less than 0.02). It was also noted that increasing age in men was associated with an increasing percentage of mouth ventilation (r = 0.83 p less than 0.03) but this relationship was not observed in women. We conclude that mouth breathing may be associated with apneas during sleep and that breathing through the mouth occurs commonly in men, particularly in those who are older. This suggests that nasal breathing may be important in the maintenance of ventilatory rhythmicity during sleep.

Many asthmatics complain of increased symptoms, awakenings, and need for additional medications during the sleeping hours. Sustained-release theophylline (THEO) may be superior to conventional inhaled bronchodilators in preventing nocturnal asthma symptoms and the early morning decrement in lung function common to this population. However, recent studies have demonstrated that THEO may delay sleep onset and perturb sleep stage distribution. No previous study has evaluated electroencephalographic, cardiac, and gas exchange indices during sleep in asthmatics treated with THEO compared with a long-acting inhaled beta 2-agonist. The study goals were to determine if theophylline perturbed sleep when compared with beta 2-agonists and to determine which agent achieved best control of daytime and nocturnal pulmonary symptoms and lung dysfunction. We evaluated 26 subjects with mild to moderate asthma and a history of frequent nocturnal symptoms who previously demonstrated decrements in AM lung function. THEO was compared with 3 puffs every 8 h (6 A.M., 2 P.M., and 10 P.M.) of bitolterol (BITOL), a long-acting beta 2-agonist, in a randomized, double-blind, placebo-controlled cross-over study. Each drug was administered for a 2-wk period ending with two consecutive nights of sleep evaluation followed by cross-over to the alternate drug regimen. During THEO administration, plasma concentrations on awakening were 11.4 +/- 0.69 micrograms/ml as compared with 0.00 micrograms/ml during BITOL. THEO was not found to disrupt sleep as sleep latency, total sleep time, percentage of total sleep time spent in Stages 1, 2, and 3/4 and in REM sleep were similar during each regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Frequently, patients with COPD with similar spirometric impairment have marked differences in dyspnea and exercise limitation. As the classic "blue bloater" with attenuated respiratory drive is described as being less dyspneic than his "pink puffer" counterpart, we wondered whether the variability in dyspnea and exercise tolerance in a group of patients with COPD with relatively similar degrees of air-flow obstruction might be partly explained by the variability in resting respiratory drives (unstimulated P0.1 and hypoxic and hypercapnic P0.1 responses). Therefore, we measured unstimulated mouth occlusion pressure (P0.1), hypoxic response (-delta P0.1/delta SaO2), hypercapnic response (delta P0.1/delta PCO2), 6-min walk distance, VO2max, steady-state exercise VE/VO2, exercise SaO2, and dyspnea using an oxygen cost diagram in 15 subjects with severe COPD (mean FEV1% 35.2 +/- 1.9 SEM). No correlations between spirometric impairment and either dyspnea or exercise performance were seen. Unstimulated P0.1 correlated inversely with spirometric impairment but did not correlate with dyspnea, VO2max or 6-min walk distance. Both hypoxic and hypercapnic responses were significantly correlated with greater exercise ventilation (VE/VO2), less exercise O2 desaturation, and a greater VO2max, but not with dyspnea or 6-min walk distance. The results of this study do not support the concept that depressed respiratory drives are associated with less dyspnea or greater exercise capability in COPD.

Ventilatory drives are presumed to be important in the maintenance of ventilation during sleep. Although the hypercapnic ventilatory response has been shown to decrease during sleep, the hypoxic ventilatory response (HVR) has not been well studied in humans. We therefore measured the ventilatory response to isocapnic hypoxia in 6 sleeping men. The HVR, measured as the slope of the relation between ventilation and decreasing hemoglobin saturation, was significantly lower in all sleep stages than in wakefulness (1.07 +/- 0.19 SEM L/min/%saturation). The HVR decreased to two thirds of this waking value in non-REM sleep (0.63 +/- 0.09 L/min/%saturation) with a further significant decrease in REM sleep when HVR was less than one third of the waking value (0.33 +/- 0.04 L/min/%saturation). The decreased HVR may help to explain the REM-sleep-related hypoxemia found in normal persons and patients with various cardiovascular diseases.

Sleep apnea syndromes and nonapneic arterial oxygen desaturation during sleep are reported more commonly in men than in women. Because men have recently been shown to have a considerably reduced hypoxic ventilatory response (HVR) during sleep, we questioned if this finding would apply to women as well. Accordingly, we measured isocapnic hypoxic responsiveness in 6 normal women during wakefulness and all stages of sleep during both follicular and luteal phases of the menstrual cycle. During non-REM sleep, women were found to maintain their waking levels of HVR, measured as the slope of the relationship between ventilation and decreasing hemoglobin saturation. Hypoxic ventilatory response fell to 70% of the awake value during REM sleep, which was a significant change (p less than 0.05). Although HVR tended to be greater in the luteal than in the follicular phase of the menstrual cycle, both awake and asleep, this was significant only in Stage 2 sleep (p less than 0.05). When compared with recently reported men studied in this laboratory, these women demonstrated significantly less awake HVR even when corrected for body surface area (p less than 0.05). During sleep men and women had similar hypoxic responses, although this represents a considerable decrement in the awake response in the men and little change in the women. How these findings relate to the observed sexual differences in "sleep disordered breathing" is speculative.