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Study objectives Repeated episodes of upper-airwayocclusion are the main characteristics of patients with obstructivesleep apnea (OSA) during sleep. It has been reported that an impairmentin the sensation of detection and a depression of ventilatorycompensation to added load could be observed in such patients. In thisstudy, we examined patients with OSA to evaluate the inspiratory effortsensation (IES), ventilation, and mouth occlusion pressures duringadded resistive loading while awake and to determine whether they canbe reversed by nasal continuous positive airway pressure (CPAP)treatment. Design A hospital-based case-controlstudy. Setting A sleep laboratory of a medical unitin Japan. Subjects Seventeen patients with moderateto severe OSA and 10 control subjects were included in this study. Measurements All patients with OSA had undergone standardnocturnal polysomnography. Patients with OSA and control subjects wereevaluated for IES measured by a modified Borg score, ventilation, andmouth occlusion pressure during control and inspiratory resistiveloaded breathing. These tests were repeated in all patients with OSAafter 2 weeks of nasal CPAP treatment. Results IES toinspiratory resistive loading was lower in patients with OSA than incontrol subjects. There were no differences in ventilation and mouthocclusion pressure between patients and control subjects during loadedbreathing. After 2 weeks of nasal CPAP, the decreased IES was increasedin patients with OSA. Conclusion In patients withOSA, the decreased IES to inspiratory resistive loaded breathing isreversible with nasal CPAP. This could be one additional benefit ofnasal CPAP in the treatment of OSA.

This study was aimed to examine the short- and long-term effects of nasal continuous positive airway pressure (CPAP) on the chemosensitivity to hypoxia and hypercapnia in the patients with obstructive sleep apnea (OSA). Awake ventilatory responses to hypoxia and hypercapnia were examined in 28 patients (3 female) with moderate to severe OSA. All these tests were examined before and after 2 weeks of nasal CPAP. In 10 patients these tests were repeated after 3-6 months of nasal CPAP. All were also tested for spirometry and arterial blood gas analysis. Patients were middle-aged (48.9 +/- 9.9 years) and their mean apnea-hypopnea index was 58.3 +/- 20.4/hour. After 2 week of nasal CPAP, PaO2 significantly increased (77.7 +/- 11.8 vs. 84.6 +/- 9.8 mmHg) and PaCO2 significantly decreased (44.9 +/- 3.8 vs. 42.3 +/- 3.7 mmHg). The ventilatory response to hypoxia significantly decreased (0.80 +/- 0.51 vs. 0.61 +/- 0.51 liter/min/%) whereas the ventilatory response to hypercapnia significantly increased after 2 weeks (1.47 +/- 0.73 vs. 1.80 +/- 0.76 liter/min/mmHg). Similar findings were also observed after 3-6 months of nasal CPAP in 10 OSA patients. Nasal CPAP treatment can alter the ventilatory responses in patients with OSA.

The exact nature of asleep blood pressure in relation to awake blood pressure is still unclear in patients with obstructive sleep apnoea. This study aimed: 1) to investigate the asleep blood pressure in both apnoeic and ventilatory periods; 2) to determine the diurnal and nocturnal factors correlated with the changes in blood pressure from apnoea to ventilatory periods during sleep. Thirty-two patients, newly diagnosed as moderate to severe obstructive sleep apnoea with a standard nocturnal polysomnography, were enrolled. The blood pressure was monitored by using the noninvasive continuous monitoring method during polysomnographic study. The mean blood pressures in ventilatory periods during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were 117.5+/-17.9 mm Hg and 128.8+/-21.9 mm Hg, and those in apnoea periods were 94.5+/-15.4 mm Hg and 102.7+/-19.0 mm Hg. The average blood pressure during NREM sleep (103.0+/-16.1 mm Hg) was higher than the awake blood pressure (97.0+/-15.7 mm Hg). The blood pressure during REM sleep was greater than that during NREM sleep. The changes in the nocturnal blood pressure from apnoea to ventilatory periods were inversely correlated with the age and nocturnal mean nadir saturation. In conclusion, patients with obstructive sleep apnoea have higher asleep blood pressure than awake blood pressure.

The aim of this study was to examine the volume-pressure (V-P) characteristics of isolated upper airways in normal subjects and patients with obstructive sleep apnoea (OSA) and to ascertain whether an increase in upper airway muscle activity affects these characteristics. We studied upper airway pressure changes during volume changes by inflation and deflation of air volumes of 5, 10, 15 and 20 mL without and with submental electrical stimulation, during voluntary closing of the glottis, in seven normal subjects and 13 OSA patients. Volume-pressure properties of the upper airway were assessed by elastance (Euaw) which was obtained from the slope of the regression line of the V-P relationships. Euaw in OSA patients was 0.52 +/- 0.08 cmH2O/mL, which was greater than in normal subjects (0.26 +/- 0.06 cmH2O/mL). Submental stimulation increased Euaw in both OSA patients and normal subjects (0.70 +/- 0.11 cmH2O/mL and 0.41 +/- 0.11 cmH2O/mL, respectively). These results suggest that upper airways of OSA patients during wakefulness are less collapsible than those of normal subjects, and that, in both groups, submental stimulation may stiffen the upper airway.

We studied submental stimulation on supraglottic resistance (Rsg) in 5 normals and 6 patients with obstructive sleep apnea. We then examined the most effective sites of stimulation in the submental regions, and the relationships between Rsg and stimulation frequency and voltage in the supine position. Inspiratory and expiratory Rsg's were obtained as the slope of the linear portion of the pressure-flow relation determined at zero flow. Before stimulation, inspiratory and expiratory Rsg's were 0.76 ± 0.06 (means ± SE) and 0.61 ± 0.02 cmH2O · L−1 · sec, respectively, in normals, and 1.04 ± 0.20 and 0.92 ± 0.29 cmH2O · L−1 · sec, respectively, in patients. Stimulation in the proximal half submental region with surface electrodes 1 cm apart decreased inspiratory and expiratory Rsg's in patients, and inspiratory Rsg in normals. Inspiratory Rsg measured in this submental region showed a stimulation frequency-and voltage-dependency in both groups, but expiratory Rsg did not. These findings suggest that submental stimulation in the proximal half region widens the supraglottic airway during mouth breathing and probably involves the upper airway muscles.

A 31-year-old male with obstructive sleep apnea syndrome was treated with KTP/532 laser midline glossectomy. He had complained of severe snoring and hypersomnolence for 2 years and sleep apnea for 1 year. His apnea index (Al) was 65.0 events/h and the lowest arterial O2 saturation (SaO2) was 44%. Cephalometric analysis and flexible fiberoptic pharyngeal endoscopy during Muller's maneuver indicated that the space-occupying sites responsible for sleep apnea were at two different levels (oropharynx-soft palate and hypopharynx-base of the tongue). The application of KTP/532 laser to midline glossectomy with uvulopalatopharyngoplasty caused slight bleeding but no obvious complications. Postoperative respiratory parameters were greatly improved: Al 5.5 and lowest SaO2 85%. Cephalometric and fiberoptic findings showed an enlarged pharyngeal space at the level of the base of the tongue. Sleep-related complaints disappeared completely.

BACKGROUND--Cyclical changes in systemic blood pressure occur during apnoeic episodes in patients with obstructive sleep apnoea (OSA). Although several factors including arterial hypoxaemia, intrathoracic pressure changes, and disruption of sleep architecture have been reported to be responsible for these changes in blood pressure, the relative importance of each factor remains unclear. This study assessed the role of hypoxaemia on the increase in blood pressure during apnoeic episodes. METHODS--The blood pressure in apnoeic episodes during sleep and the blood pressure response to isocapnic intermittent hypoxia whilst awake were measured in 10 men with OSA. While asleep the blood pressure was measured non-invasively using a Finapres blood pressure monitor with polysomnography. The response of the blood pressure to hypoxia whilst awake was also measured while the subjects intermittently breathed a hypoxic (5% or 7% oxygen) gas mixture. Each hypoxic gas exposure was continued until a nadir arterial oxygen saturation (nSaO2) of less than 75% was reached, or for a period of 100 seconds. The exposure was repeated five times in succession with five interposed breaths of room air in each run. RESULTS--The mean (SD) increase in blood pressure (delta MBP) during apnoeic episodes was 42.1 (17.3) mm Hg during rapid eye movement (REM) sleep and 31.9 (12.5) mm Hg during non-REM sleep. The delta MBP during apnoeic episodes showed a correlation with the decrease of nSaO2 (delta SaO2) (r2 = 0.30). The change in blood pressure in response to intermittent hypoxia whilst awake was cyclical and qualitatively similar to that during apnoeic episodes. Averaged delta MBP at an SaO2 of 7% and 5% oxygen was 12.6 (5.7) and 13.4 (3.6) mm Hg, respectively, whereas the averaged delta MBP at the same delta SaO2 during apnoeic episodes was 38.4 (15.5) and 45.2 (20.5) mm Hg, respectively. CONCLUSIONS--The blood pressure response to desaturation whilst awake was about one third of that during apnoeic episodes. These results suggest that factors other than hypoxia may play an important part in raising the blood pressure during obstructive sleep apnoea.

It is known that the ventilatory response to carbon dioxide (CO2) is increased in asthmatics with airway obstruction. Increased vagal afferent activity as well as increased airway resistance have been postulated as the causative mechanisms. However, whether increased vagal afferent activity without bronchoconstriction increases the ventilatory response to CO2 has not been investigated in humans. We examined the effects of prostaglandin E2 (PGE2) inhalation, which is known to stimulate vagal afferent receptors in the lung without an increase in airway resistance, on the respiratory response to CO2 in seven healthy male subjects. Either physiologic saline or PGE2 (100 micrograms/ml) was inhaled through a Bird nebulizer for 3 min. Twenty minutes after each inhalation, the responses of minute ventilation (VE) and occlusion pressure (P0.1) to hyperoxic hypercapnia were measured. Both the relationships between VE and P0.1 to an increase in tension of end-tidal CO2 (PETCO2) were analyzed by linear regression. Although the mean value of respiratory resistance after PGE2 (3.0 cm H2O/L/s +/- 0.4) did not differ significantly from that after saline (3.1 cm H2O/L/s +/- 0.4), inhaled PGE2 significantly increased the hypercapnic response. This result suggests that the increased vagal afferent activity per se plays an important role in increasing the hypercapnic ventilatory response in humans.

We measured electromyograms (EMGs) of genioglossus muscle (GG) and inspiratory intercostal muscle (IIM) in both rapid eye movement (REM) sleep and non-REM sleep of 12 patients with obstructive sleep apnea (OSA) to examine the influence of different sleep stages on upper airway muscle activity during sleep apnea. Quantifications of both muscle activities were assessed by their individual peak amplitude of integrated inspiratory EMG. Genioglossus and IIM activities showed a qualitatively similar cyclic change with an alteration of apneic and ventilatory phases during both non-REM and REM sleep. Both muscle activities increased gradually in the late apneic phase and reached each peak at the opening of the upper airway and, subsequently, decreased gradually. There were no significant differences in both muscles activities in either the ventilatory or early apneic phase between non-REM sleep and REM sleep. On the other hand, GG and IIM activities in the late apneic phase during REM sleep were significantly lower than those during non-REM sleep. The relative activity of GG to IIM in the late apneic phase was significantly lower during REM sleep than that during non-REM sleep. These results indicate that upper airway and intercostal muscle activation in the later apneic phase during REM sleep were inhibited compared with those during non-REM sleep and that this inhibition was observed predominantly in upper airway muscles.

1. An attempt has been made to test the hypothesis that, in the caudal part of nucleus tractus solitarii (NTS) where carotid sinus nerve (CSN) afferents project, L-glutamate (Glut) modulates the hypoxic ventilatory response. 2. Unanaesthetized, peripherally chemodenervated (carotid body denervated; CBD) and sham-operated, freely moving rats were used. During peripheral chemoreceptor stimulation by hypoxia (10% O2 for 30 min) or doxapram (Dox) infusion (2 mg kg-1 (30 min)-1), ventilation was recorded and successively, under the same conditions, the extracellular Glut concentration ([Glut]o) in the caudal NTS was measured by in vivo microdialysis. [Glut]o was also measured during hyperoxic hypercapnia (10% CO2-30% O2 for 30 min). 3. Furthermore, the effects on ventilation of exogenous Glut, the NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 or the ionotropic receptor antagonist kynurenate microinjected into the caudal NTS were investigated in sham-operated rats. 4. In sham-operated rats, both ventilation and [Glut]o in NTS were increased during peripheral chemoreceptor stimulation. On the other hand, no increases in either ventilation or Glut release were observed in CBD rats. In spite of ventilatory augmentation during hypercapnia, no response of [Glut]o to hypercapnia was observed in either group. 5. Local Glut application into NTS increased ventilation. Pretreatment with MK-801 or kynurenate reduced the hypoxic ventilatory response. This reduction in ventilation was mainly due to the decrease in tidal volume. 6. These results suggest that hypoxia induced the release of Glut in NTS and that this effect was mediated by arterial chemosensory input.

Many deaths from attacks of asthma may be preventable. However, the difficulty in preventing fatal attacks is that not all the pathophysiologic risk factors have been identified.To examine whether dyspnea and chemosensitivity to hypoxia and hypercapnia are factors in fatal asthma attacks, we studied 11 patients with asthma who had had near-fatal attacks, 11 patients with asthma who had not had near-fatal attacks, and 16 normal subjects. Their respiratory responses to hypoxia and hypercapnia, determined by the standard rebreathing technique while the patients were in remission, were assessed in terms of the slopes of ventilation and airway occlusion pressure as a function of the percentage of arterial oxygen saturation and end-tidal carbon dioxide tension, respectively. The perception of dyspnea was scored on the Borg scale during breathing through inspiratory resistances ranging from 0 to 30.9 cm of water per liter per second.The mean (+/- SD) hypoxic ventilatory response (0.14 +/- 0.12 liter per minute per percent of arterial oxygen saturation) and airway occlusion pressure (0.05 +/- 0.05 cm of water per percent of arterial oxygen saturation) were significantly lower in the patients with near-fatal asthma than in the normal subjects (0.60 +/- 0.35, P0.001, and 0.16 +/- 0.08, P0.001, respectively) and the patients with asthma who had not had near-fatal attacks (0.46 +/- 0.29, P = 0.003, and 0.15 +/- 0.09, P = 0.004). The Borg score was also significantly lower in the patients with near-fatal asthma than in the normal subjects, and their lower hypoxic response was coupled with a blunted perception of dyspnea.Reduced chemosensitivity to hypoxia and blunted perception of dyspnea may predispose patients to fatal asthma attacks.

To examine the effects of sustained hypoxia on upper airway and chest wall muscle activity in humans, we measured genioglossus muscle (GG) activity, inspiratory intercostal muscle (IIM) activity, and ventilation during sustained hypoxia in 17 normal subjects and 17 patients with obstructive sleep apnea (OSA). The trial of sustained hypoxia was performed as follows: after an equilibration period of 3 min, isocapnic hypoxia (arterial O2 saturation = 80 +/- 2%) was maintained for 20 min. GG EMG was measured with a fine-wire electrode inserted percutaneously, and IIM EMG was measured with surface electrodes. Ventilatory response to sustained hypoxia was initially increased and subsequently decreased. Stable phasic GG activity during spontaneous tidal breathing was observed in 6 normal subjects and 10 patients with OSA. Responses of GG and IIM activities to sustained hypoxia showed a biphasic response qualitatively similar to the ventilatory response in these 16 subjects. The absolute value of the subsequent decline in GG activity was similar to that of the initial increase, whereas the subsequent decline in IIM activity was smaller than that of the initial increase. Percent GG activity was significantly lower than both percent IIM activity and percent minute ventilation during the decline and plateau phases. There were no significant differences in ventilatory and EMG responses between the normal subjects and the patients with OSA. We conclude that, during wakefulness, upper airway muscle activity declined to a greater extent than inspiratory pump muscle activity during sustained hypoxia.

Upper airway dilating muscle activity increases during apneic episodes in patients with obstructive sleep apnea (OSA). To elucidate the relative contribution of chemical and nonchemical stimuli to augmentation of the upper airway dilating muscle, we measured the response of genioglossus muscle (GG) and inspiratory intercostal muscle (IIM) activities to obstructive apnea during non-REM sleep and compared them with the response to progressive hypoxia and hypercapnia during awake periods in seven male patients with OSA. GG EMG was measured with a wire electrode inserted percutaneously, and IIM EMG was measured with surface electrodes placed in the second intercostal space parasternally. Responses to hypoxia and to hypercapnia were assessed by rebreathing methods in the supine position while awake. Following these measurements, a sleep study was conducted with the EMG electrodes placed in the same locations. The relationship between GG and IIM activities during the cycle of apnea and postapneic ventilation in non-REM sleep was quasi-linear, and the slope of the regression line was significantly greater than those during progressive hypoxia and progressive hypercapnia. The amplitude of GG activity at 70% of maximum IIM activities in the hypoxic test was 140 +/- 20% (mean +/- SEM) during non-REM sleep, which was also significantly greater than that during hypoxia (51 +/- 10%) and that during hypercapnia (59 +/- 15%). These results suggest that nonchemical factors contribute considerably to augmentation of GG activity during obstructive apneic episodes. The nonchemical stimuli may arise from mechanoreceptors activated by upper airway obstruction and behavioral factors associated with change in sleep states.

We examined the effect of electrical stimulation of the hypoglossal nerve and pharyngeal lubrication with artificial surfactant (Surfactant T-A) on the opening of obstructed upper airway in nine anesthetized supine dogs. The upper airway was isolated from the lower airway by transecting the cervical trachea. Upper airway obstruction was induced by applying constant negative pressures (5, 10, 20, and 30 cmH2O) on the rostral cut end of the trachea. Peripheral cut ends of the hypoglossal nerves were electrically stimulated by square-wave pulses at various frequencies from 10 to 30 Hz (0.2-ms duration, 5–7 V), and the critical stimulating frequency necessary for opening the obstructed upper airway was measured at each driving pressure before and after pharyngeal lubrication with artificial surfactant. The critical stimulation frequency for upper airway opening significantly increased as upper airway pressure became more negative and significantly decreased with lubrication of the upper airway. These findings suggest that greater muscle tone of the genioglossus is needed to open the occluded upper airway with larger negative intraluminal pressure and that lubrication of the pharyngeal mucosa with artificial surfactant facilitates reopening of the upper airway.

To determine whether the intensity of dyspnea at a given level of respiratory motor output differs between bronchoconstriction and the presence of an external resistance, we compared the sensation of difficulty in breathing during isocapnic voluntary hyperventilation in six normal subjects. An external resistance of 1.9 cmH2O.1–1.s was applied during both inspiration and expiration. To induce bronchoconstriction, histamine aerosol (5 mg/ml) was inhaled until airway resistance (Raw) increased to a level approximately equal to the subject's control Raw plus the added external resistance. To clarify the role of vagal afferents on the genesis of dyspnea during both forms of obstruction to airflow, the effect of airway anesthesia by lidocaine aerosol inhalation was also examined after histamine and during external resistive loading. The sensation of difficulty in breathing was rated at 30-s intervals on a visual analog scale during isocapnic voluntary hyperpnea, in which the subjects were asked to copy an oscilloscope volume trace obtained previously during progressive hypercapnia. Histamine inhalation significantly increased the intensity of the dyspneic sensation over the equivalent external resistive load at the same levels of ventilation and occlusion pressure during voluntary hyperpnea. Inhaled lidocaine decreased the sensation of dyspnea during bronchoconstriction with no change in Raw, but it did not significantly change the sensation during external resistive loading. These results suggest that afferent vagal activity plays a role in the genesis of dyspnea during bronchoconstriction.

The purposes of the present study were to determine the changes in functional residual capacity (FRC) during inspiratory loading and to examine their mechanisms. We studied seven normal subjects seated in a body plethysmograph. In both graded inspiratory elastic (35, 48, and 68 cmH2O/l) and resistive (21, 86, and 192 cmH2O.l-1.s) loading, FRC invariably decreased from control FRC and phasic expiratory activity increased. The reduction in FRC was greater with greater loads. A single inspiratory effort against an inspiratory occlusion at three different target mouth pressures (-25, -50, and -75 cmH2O) and durations (1, 2, and 5 s) also resulted in a decrease in FRC with an increase in expiratory electromyogram activity in the following expiration. The decrease in FRC was greater with greater target pressure and duration. This decrease in FRC is qualitatively similar to that during inspiratory loaded breathing, and we suspect that the same mechanisms are at work. Because neither vagal nor chemoreceptor reflex can account for these responses, we suspect conscious awareness of breathing or behavioral control to be responsible. In an additional study, the sensation of discomfort of breathing during elastic loading decreased with a decrease in FRC. These results suggest that the reduced FRC may be due to behavioral control of breathing to reduce the sensation of dyspnea during inspiratory loading.

Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan, First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan, Division of Pathology, School of Health Sciences, Tohoku University, Sendai, Japan, Laboratory of Molecular Pharmacology, Tohoku University School of Medicine, Sendai, Japan, Department of Cardiovascular Medicine, Tohoku University School of Medicine, Sendai

To evaluate sleep-related obstructive breathing events in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), we developed a technique for digital recording and analysis of esophageal pressure (Pes) and elucidated the Pes parameters. Pes was recorded overnight with a microtip-type pressure transducer in 74 patients with OSAHS. Simultaneously, in all patients digital polysomnography was recorded. The mean nadir end-apneic Pes swing (Pes Nadir) ranged from -20.2 to -147.4 cmH(2)O, with a mean of -53.6+/-2.9 cmH(2)O. Correlation of the mean Pes Nadir indicated a linear relationship with the mean ratio of maximal Pes swing to apnea duration (r(2)=0.70) and the mean area of the Pes (Pes Area) (r(2)=0.82). Significant correlations were noted between the mean Pes Nadir and apnea-hypopnea index (AHI, ranging from 7.9 to 109.5 per hour; r(2)=0.66), minimum SpO(2) (r(2)=0.60), oxygen desaturation index (ODI) of more than 3 (r(2)=0.65), arousal index (r(2)=0.54), and between the mean Pes Area and AHI (r(2)=0.63), minimum percutaneous arterial oxygen saturation (SpO(2); r(2)=0.57), ODI (r(2)=0.69), and arousal index (r(2)=0.41). Pes parameters were found to be significant in the evaluation of the severity of the respiratory effort during the sleep-related obstructive breathing events for patients with OSAHS.

Obstructive sleep apnea (OSA) is commonly associated with systemic hypertension and now recognized as an independent risk factor for daytime hypertension. We aimed to study the short- and long-term effect of nasal continuous positive airway pressure (CPAP) in hypertensive and normotensive patients with OSA. Forty-six patients with moderated to severe OSA were treated with nasal CPAP and followed after one year of treatment. Clinic blood pressure, heart rate, and body weight were taken before and followed up for one year after beginning nasal CPAP. In this study 25 patients with OSA were found to have hypertension (54.3%). The hypertensive group showed a significant reduction in clinic blood pressure after nasal CPAP, whereas the normotensive group showed no changes. The subgroup of hypertensive patients with OSA who had no anti-hypertensive medication revealed a decrease in clinic blood pressure comparable to those with anti-hypertensive drugs. The heart rate was not significantly changed in any patients. There was no significant correlation between the decrease in body weight and the reduction in blood pressure. These results suggest that nasal CPAP alone might have a substantial blood pressure lowering effect in hypertensive patients with OSA. This effect could decrease the morbidity and mortality related to cardiovascular complications in patients with OSA.

The purpose of this study was to examine our hypothesis that γ-aminobutyric acid (GABA) in the nucleus tractus solitarii (NTS) may be related to the hypoxic ventilatory decline (HVD) and that chemoreceptor stimulation was essential to activate this mechanism. We used unanesthetized, freely moving rats in this study. An in vivo microdialysis technique was used to measure the extracellular GABA concentration ([GABA]o), and an in vivo microinjection technique was used to examine the effects of the GABA agonists and antagonists on the ventilation during hypoxia. The GABA agonists injected into the NTS attenuated the ventilation during hypoxia. By hypoxic exposure, [GABA]o was increased during the HVD. However, by carotid body denervation (CBD), this GABA increase was abolished. Although GABA antagonists microinjected into the NTS during the HVD phase significantly increased the depressed ventilation, this effect on the ventilation was abolished by CBD. These results suggest that the GABA in the NTS has a pivotal role in the HVD and that this mechanism is not activated without chemoreceptor stimulation.

Objectives: We assessed whether hypercapnia patients with an extremely high level of PaCO2≧60 mm Hg were suitable candidates for lung volume reduction in the treatment of severe pulmonary emphysema.Methods: Of 65 patients undergoing lung volume reduction surgery between May 1993 and August 1997, 6 (9.23%) who had a preoperative rest room air blood gas level of PaCO2≧60mm Hg were selected for study. All patients underwent video-assisted thoracoscopic surgery. Of the 6 with severe hypercapnia, 5 underwent the unilateral procedure and 1 the bilateral procedure.Results: All severe hypercapnia patients showed significant clinical improvement. When assessed at 3 to 6 months after lung volume reduction surgery, significant improvements were seen in mean forced expiratory volume in 1 second (preop: 0.44±0.04 L; postop: 0.74±0.20 L; p

Dynamic changes in the pharyngea airway of patients with obstructive sleep apnea syndrome (OSAS) were evaluated by quantitating the findings of real-time imaging performed during wakefulness and spontaneous sleep by means of dynamic magnetic resonance imaging (MRI). Six patients with OSAS and 3 non-OSAS subjects, selected prospectively and randomly, underwent polysomnography and dynamic MRI. The cross-sectional areas of the soft palate and oropharynx and the anterior-posterior airway dimensions seen during wakefulness and spontaneous sleep were calculated by US National Institutes of Health imaging software. On the basis of a case control study, comparisons were made with age-matched and body mass index—matched obese non-OSAS snorers. Spontaneous sleep caused significant obstruction and narrowing of various sites of the pharyngeal airway in the OSAS patients, but not in the non-OSAS subjects. During wakefulness, the non-OSAS subjects showed no marked narrowing of the pharyngeal airways, whereas a transient but significant narrowing was observed in the OSAS patients. The mean values of both the cross-sectional area and the anterior-posterior diameter at the soft palate were significantly reduced by spontaneous sleep in the OSAS patients. Dynamic MRI in awake OSAS patients shows promise as a routine diagnostic tool for localizing the upper airway collapse for appropriate selection of surgical therapy.

Dyspnea may be one of the defense systems of our body, like pain or other sensations. Accordingly, if the perception of dyspnea is lost or blunted in patients with asthma, it could be dangerous. In this study, to examine the mechanisms of death from asthma and to elucidate the important role of the dyspnea sensation in preventing death from asthmatic attack, we performed two studies. First, we examined the perception of dyspnea and the chemosensitivity to hypoxia and hypercapnia in 11 patients with a history of near-fatal asthma (NFA). Second, we also examined circumstances of life-threatening attacks or triggering factors of unconsciousness by interviewing 20 patients with NFA. The hypoxic responses of patients with NFA were significantly decreased as compared with those of the normal subjects and the patients with usual asthma. By contrast, there were no significant differences in the hypercapnic responses among the three groups. Dyspnea sensation measured with the Borg score while breathing though graded resistances, was also significantly lower in the patients with NFA than in the normal subjects. In addition, most of the patients with NFA had lost consciousness due to increasing physical activity or inhalation of β2-stimulants through an ultrasonic nebulizer. They did not feel severe suffocation before losing consciousness. These results suggest that (1) lowered hypoxic chemosensitivity and blunted perception of dyspnea may predispose patients to life-threatening attacks and that (2) severe hypoxemia induced by increasing physical activity may be a primary cause of losing consciousness, leading to death.

This study was conducted to investigate the correlation of thoracoscopic lung volume reduction to changes in pulmonary function and exercise performance in patients with pulmonary emphysema. Unilateral thoracoscopic lung volume reduction treatment was performed in 30 patients with severe pulmonary emphysema. If large bullae were present, they were excised using an endoscopic stapling device, and the emphysematous pleura was contracted by neodymium:yttrium-aluminium-garnet laser to reduce the volume of nonfunctional lung air space. Pulmonary function and incremental exercise tests were performed before and at least 3 months after treatment. Follow-up functional evaluation showed a highly significant improvement in the forced expiratory volume in 1s (FEV1), forced vital capacity, static compliance, and maximal oxygen uptake. The functional residual capacity as measured by the gas dilution method (FRCgas), was unchanged; however, it was found to be decreased significantly when measured by body plethysmograph (FRCbox). Positive correlations existed between the reduction in FRCbox and the increase in FEV1 (r = 0.586, P = 0.0042) and maximal oxygen uptake (r = 0.550, P = 0.018). Pulmonary ventilation and exercise ability in patients with pulmonary emphysema were improved in a volume-dependent manner by thoracoscopic lung volume reduction. These findings indicate that patients with a preoperative trapped gas volume level exceeding 11 would be ideal candidates for thoracoscopic lung volume reduction.

The prevalence of sleep apnea syndrome (SAS) is approximately 7.5% in Japanese adults aged 18-68 years old. SAS is characterized by repeated episodes of apnea, especially obstructive apnea, during sleep. Severe SAS has life-threatening complications such as pulmonary hypertension, arrhythmias, right heart failure or brain damage, which could be caused by hypoxemia and/or hypercapnia. Upper airway relaxation is responsible for the obstruction during apnea, and an increase in the activities of the upper airway muscles dilates and stiffens the upper airway wall. Maintaining the activities of the upper airway muscles may contribute to keeping the airway patent. Submental electrical stimulation of the upper airway muscles would be a novel treatment method for obstructive apnea.

We assessed the effect of sustained isocapnic hypoxia (PCO2 = 40 Torr, SaO2 = 80%) on the sensation of dyspnea in 16 normal healthy males. Subjects rated the sensation of dyspnea (c) on 15 cm visual analog scales during 20 min of sustained hypoxia. Following this hypoxic period, 8 subjects undertook mild exercise (10-50 W on a bicycle ergometer for 3 min) under the continuation of hypoxia. During sustained hypoxia, psi increased initially with ventilation from 0.6 +/- 0.2 (n = 16, mean +/- SE) to 2.9 +/- 0.6 at peak ventilation, but it decreased with ventilatory depression to 1.6 +/- 0.4. Dyspnea intensity during hypoxic exercise was significantly smaller than that at peak ventilation in the resting hypoxic period (2.3 +/- 0.7 vs. 3.9 +/- 1.0), although the ventilation was greater during exercise (24.0 +/- 3.0 vs. 19.7 +/- 1.4 l/min). These results indicate that sustained hypoxia has a biphasic, i.e., initial stimulatory and delayed depressant, effect on dyspnea and on ventilation. It is suggested that the dyspnea sensing mechanism is suppressed during mild exercise under sustained hypoxia.

We examined the effects of nasal continuous positive airway pressure (CPAP) on exercise performance in patients with obstructive sleep apnea (OSA). Six patients were treated with nasal CPAP on seven successive days and underwent overnight sleep studies and multiple sleep latency test (MSLT) at the beginning and after the last day of the treatment. The subjects also performed incremental exercise testing using a bicycle ergometer followed by 0-w, 25-w, 50-w,--(3 minutes each) until maximum level. Arterial oxygen pressure, arterial carbon dioxide pressure at rest while awake, apnea/ hypopnea index, longest apnea duration, the lowest percutaneous oxygen saturation measured by a pulse oximeter and the value of MSLT were significantly improved after nasal CPAP. Moreover, maximal oxygen consumption was significantly increased from 1841 ml/min +/- 350 to 2125 ml/min +/- 351 (p < 0.05); however, other cardiorespiratory parameters did not change significantly. The improvement of exercise performance by short-term nasal CPAP treatment in OSA patients may correlate with the improvement of sleepiness.

We examined changes in the blood flow velocity of brain stem artery (BSA) and middle cerebral artery (MCA) in response to hypercapnic, normocapnic and hypocapnic hyperventilation in seven awake subjects with a transcranial Doppler to determine if there are differences in blood flow control in regional brain perfused by these respective arteries, and to separate the effects of CO 2 and ventilation itself on blood flow velocity during CO 2 loading. During hypercapnic hyperventilation, BSA flow velocity increased linearly with an increase in end-tidal partial pressure of CO 2 ( Pet CO 2 ). During hypocapnic hyperventilation, BSA flow velocity decreased linearly with decrease in Pet CO 2 , but did not change during normocapnic hyperventilation. The mean CO 2 reactivity of BSA was 2.8% / mmHg. The responses of MCA to these hyperventilations and CO 2 reactivity were similar to those of BSA. These findings suggest that CO 2 rather than ventilation per se is the important stimulus to changes in brain blood flow velocity and that the CO 2 responses of brain arteries are not affected by differences in vascular beds.

Recent reports suggest the involvement of vascular phenomena in exercise-induced asthma. Sensory neuropeptides, such as substance P (SP), which causes airway vascular dilatation and plasma leakage, have been demonstrated to play a role in hyperpnea-induced airway narrowing in animal studies. The purpose of this study was to investigate the importance of tachykinins in exercise-induced airway narrowing in patients with asthma using a selective neurokinin 1-receptor (NK1-receptor) antagonist, FK-888. In a double-blind, placebo-controlled, crossover trial, nine subjects with stable asthma were given FK-888 (2.5 mg) or placebo by inhalation 20 min before each exercise at a level previously demonstrated to cause a fall of at least 40% in specific airway conduction (SGaw). Inhalation of FK-888 had no significant effect on baseline SGaw. While the recovery from exercise-induced airway narrowing was significantly faster after treatment with FK-888 the area under the curve for SGaw during the 50 min after exercise was significantly reduced (p0.05) and the time taken for the SGaw to recover to within 65% of baseline after exercise was also significantly shorter with FK-888 than the placebo (p0.05). However, treatment with FK-888 did not significantly attenuate the maximal fall in SGaw. These results suggest that NK1-receptor-mediated mechanisms are involved in the recovery phase of exercise-induced airway narrowing. The possible mechanisms of these phenomena are discussed.

1. The parabrachial nucleus (PBN) is thought to play an important role in cardiorespiratory control. However, the circumstances under which it affects ventilation are still not known. The purpose of the present study was to investigate how the PBN modulates the ventilatory responses to hypercapnia, hypoxia or a resistive load in awake rats with chemical lesions of the PBN. 2. In three groups of rats (with lateral PBN lesion, with Kolliker-Fuse nucleus lesion and control), ventilation was measured under various conditions. 3. There was no difference in the breathing of normal room air in any of the groups. However, the lesioned groups showed a reduced ventilatory response to hyperoxic hypercapnia (inspired CO2 fractions (FI,CO2) of 3, 5, 8 and 10%) and to graded hypoxia (inspired O2 fractions (FI,O2) of 16, 12, 10 and 8%) compared with the control group. The control group showed a biphasic response to sustained hypoxia (FI,O2 at 10% for 30 min), known as 'hypoxic depression', while the lesioned groups showed moderate ventilatory exaggeration throughout hypoxia. In response to a resistive load, the lateral PBN lesion group showed no change in ventilatory compensation. 4. The PBN appeared to have a considerable influence on ventilation stimulated in various ways during wakefulness.

1. We examined the role of nitric oxide (NO) in respiratory regulation in the nucleus tractus solitarii (NTS), where L-glutamate release associated with peripheral chemoreceptor activation modulates the hypoxic ventilatory response. 2. Experiments were performed in unanaesthetized freely moving rats. First, the effects on the hypoxic ventilatory response of sodium nitroprusside (SNP, a NO donor) or NG-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor), microinjected into the NTS, were investigated. Second, using in vivo microdialysis, changes in extracellular L-glutamate during hypoxia were examined in the presence of L-NMMA. Third, the effect of L-NMMA on ventilatory augmentation by exogenous L-glutamate was examined. Furthermore, we measured extracellular L-citrulline concentration changes during hypoxia in the NTS to assess NO formation indirectly and also examined the effect of MK-801 (an NMDA receptor antagonist) on L-citrulline levels during hypoxia. 3. SNP increased ventilation during both normoxia and hypoxia. L-NMMA did not alter ventilation or L-glutamate levels during normoxia but significantly attenuated the hypoxic ventilatory response and the increase in L-glutamate during hypoxia. The inhibition by L-NMMA was blocked by L-arginine. The ventilatory augmentation by exogenous L-glutamate was attenuated by L-NMMA. L-Citrulline increased during hypoxia, and this increase was inhibited by MK-801. 4. We provide the first in vivo evidence that, in the NTS, NO works as a retrograde messenger in an L-glutamate-releasing positive feedback system contributing to the augmentation of ventilation during hypoxia.

To determine the effects of electrical hypoglossal nerve and submental stimulation on upper airway collapsibility, we examined the pressure-volume (P-V) relationships during bilateral supramaximal stimulation of the distal cut hypoglossal nerve ends over a range of frequencies from zero to 100 Hz in the sealed upper airway of 10 anesthetized supine dogs. Animals were artificially ventilated with 50% O2 and maintained under relative hyperoxia and hypocapnia during the study to eliminate the ventilatory drive output. Sealed upper airway pressures were obtained during random injections of different volumes of air from zero to 50 ml with and without hypoglossal nerve stimulation, and the upper airway P-V curves were obtained. The characteristics of the P-V curves were as follows: (1) the upper airway compliance defined as the slope of the regression of P-V curves fell from 4.07 +/- 0.33 ml/cm H2O without stimulation to 3.02 +/- 0.30 ml/cm H2O with stimulation at 50 Hz and plateaued at frequencies greater than 50 Hz, and (2) the volume at a given pressure during stimulation was larger than that without stimulation. The effects of submental stimulation on upper airway collapsibility were similar to those of hypoglossal nerve stimulation. These results suggest that the increase of upper airway muscle tone by hypoglossal nerve or submental stimulation stiffens the upper airway and that increases in muscle tone expand the upper airway.

To map the superficial locations which are involved in the control of respiration and tracheal smooth muscle tone in ventrolateral medulla, we examined the effects of local anesthesia on phrenic activity and tracheal tone in twelve anesthetized, paralyzed, and artificially ventilated dogs. 0.5 microliter of 5% procaine was injected 0.3 to 0.5 mm below the surface unilaterally to the ventral superficial layer (from the rostral part of the trapezoid body to the caudal hypoglossal rootlets and lateral from the pyramids to 5.5 mm from the midline), which included rostral, intermediate and caudal areas, and the area lateral to the hypoglossal rootlets. The peak amplitude of the integrated phrenic neurogram was decreased by procaine injection to the intermediate area and the area lateral to the hypoglossal rootlets. Tracheal tone decreased only by procaine injection to the intermediate area. In the intermediate area, some injections decreased either phrenic output alone or tracheal tone alone. These results suggest that the two ventral medullary areas, i.e. the intermediate and caudolateral parts, contain neural structures which are involved in the shaping of phrenic output, but only the intermediate area is involved in the regulation of tracheal tone. It is also suggested that, in the intermediate area, the structures responsible for the maintenance of respiration and tracheal tone are, at least in part, separable.

BACKGROUND--It has previously been reported that short term submental stimulation can reduce the frequency of apnoea and improve sleep architecture in patients with obstructive sleep apnoea. The effects of submental stimulation during consecutive nights on apnoea or on daytime sleepiness have not, however, been studied. METHODS--Patients with obstructive sleep apnoea were studied by polysomnography on a control night, for five consecutive nights of submental stimulation, and on three following nights (n = 8). A multiple sleep latency test (MSLT) (n = 8) and measurement of the upper airway resistance (n = 5) were performed during the day after the polysomnographic study, on the control night, and on the fifth stimulation night. In an additional five patients with obstructive sleep apnoea, matched for age, sex, and weight, the effects of two nights of stimulation were examined for comparison. Submental stimulation began when an apnoea lasted for five seconds and stopped with the resumption of breathing as detected by oronasal flow. RESULTS--The apnoea index, the number of times per hour that SaO2 dropped below 85% (SaO2 < 85%/hour), and the total apnoea duration expressed as a percentage of total sleep time during stimulation nights decreased to approximately 50% of the corresponding values on the control night. This improvement persisted for at least two nights after the five consecutive stimulation nights, but not after the two consecutive stimulation nights. Sleep architecture and MSLT following the stimulation nights improved but upper airway resistance did not change. CONCLUSIONS--Submental stimulation for five consecutive nights in patients with obstructive sleep apnoea improved the breathing disturbance, sleep quality, and daytime sleepiness. The effect lasted for the following two nights, but did not completely abolish the sleep disordered breathing.

BACKGROUND--It is well known that upper airway resistance increases with postural change from a sitting to supine position in patients with obstructive sleep apnoea (OSA). It is not known, however, how the postural change affects the ventilatory and occlusion pressure response to hypercapnia in patients with OSA when awake. METHODS--The responses of minute ventilation (VE) and mouth pressure 0.1 seconds after the onset of occluded inspiration (P0.1) to progressive hypercapnia (delta VE/delta PCO2, delta P0.1/delta PCO2) both in sitting and supine positions were measured in 20 patients with OSA. The ratio of the two (delta VE/delta P0.1) was obtained as an index of breathing efficiency. The postural changes in response to carbon dioxide (CO2) after uvulopalatopharyngoplasty (UPPP) were also compared in seven patients with OSA. RESULTS--There were no significant changes in the resting values of end tidal PCO2, P0.1, or VE between the two positions. During CO2 rebreathing, delta VE/delta PCO2 did not differ between the two positions, but delta P0.1/delta PCO2 was significantly higher in the supine than in the sitting position (supine, mean 0.67 (SE 0.09) cm H2O/mm Hg; sitting, mean 0.57 (SE 0.08) cm H2O/mm Hg), and delta VE/delta P0.1 decreased significantly from the sitting to the supine position (sitting, 4.6 (0.4) l/min/cm H2O; supine, 3.9 (0.4) l/min/cm H2O). In seven patients with OSA who underwent UPPP, delta VE/delta P0.1 improved significantly in the supine position and postural change in delta VE/delta P0.1 was eliminated. CONCLUSIONS--These results suggest that in patients with OSA the inspiratory drive in the supine position increases to maintain the same level of ventilation as in the sitting position, and that the postural change from sitting to supine reduces breathing efficiency. Load compensation mechanisms of patients with OSA appear to be intact while awake in response to the rise in upper airway resistance.

We developed a new portable sleep monitoring system and studied the prevalence of sleep apnea syndrome among Japanese industrial workers. This device assessed three kinds of parameters: nasal airflow, tracheal sound and electrocardiogram (ECG), and digitally stored the clock time of the onset of apnea, apnea duration and R-R intervals by a built-in microcomputer. After monitoring, the portable sleep monitor was connected to a host computer, and apneic episodes, the so-called 'apnea index' as apneic episodes corrected by measuring time ('AI') and R-R intervals were analyzed. In 170 inpatients referred to our sleep clinic, sleep monitoring by this device was performed simultaneously with all-night polysomnography, and the sensitivity and specificity of this device was determined under different criteria of the apnea index (AI) (AI5, 10, 15 and 20 episodes/h) by polysomnography. In all AI criteria, the sensitivity was more than 90%, and the specificity was also reasonably high. Using this system, successive 2-night home sleep monitoring was performed on 168 healthy workers in one Japanese industrial company, and 159 people (140 males; 19 females) who had successful monitoring were analyzed. The percentage of persons who had 'AI' of more than 10 episodes/h was 7.5%. There were no significant correlations between 'AI' and age, body weight or scores estimated by sleep questionnaires. These results suggest that even in people who are seemingly healthy significant apneic episodes could be detected by the portable home sleep monitoring system. This system may therefore be useful in evaluating the occurrence of sleep apnea syndrome in general populations.

We examined the effects of multiple repetitive airway obstruction (RAO) on arterial oxygen saturation (SaO2) and pulmonary and systemic arterial pressure in eight anesthetized spontaneously breathing dogs. SaO2 was monitored at the tongue with a pulse oximeter. RAO created by an electrical valve that was attached to a tracheal cannula was alternated with seven consecutive spontaneous breaths until the nadir SaO2 (nSaO2) became constant or decreased to less than 35%. Tracheal occlusion durations of 15, 30, 45 and 60 s were chosen arbitrarily. In each animal nSaO2 decreased with every trial number in an exponential fashion, and the rate of nSaO2 fall was greater for the longer occlusion duration. In each animal the increases in pulmonary arterial pressure (PAP) and systemic arterial pressure (SAP) were inversely related to the nSaO2 values, and the relationship between nSaO2 and PAP or SAP was identical for all occlusion durations. Moreover, when the animals breathed pure oxygen and SaO2 did not decrease, there were no significant increases in the PAP and SAP at similar levels of pleural pressure (Ppl). In another six dogs, the effects of RAO on PAP and SAP were compared with those of intermittent hypoxic exposure without apnea, which was achieved by the inhalation of hypoxic gas (4 to 6% O2, 5% CO2 in N2) instead of RAO, to examine the effects of interruption of ventilation. The relationships between nSaO2 and both pressures did not differ significantly from those during RAO.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: A high ratio of forced expiratory to forced inspiratory maximal flow at 50% of vital capacity (FEF50/FIF50) may identify upper airway dysfunction. Since hypercapnia increases the motor activity of airway dilating muscles its effects on the maximum expiratory and inspiratory flow-volume curves (MEIFV) in patients with obstructive sleep apnoea and in normal subjects in different postures was studied. METHODS: The effects of posture on the maximum expiratory and inspiratory flow-volume curves during the breathing of air and 7% carbon dioxide in 11 patients with obstructive sleep apnoea were compared with those in nine normal subjects. Measurements were made in the sitting, supine, and right lateral recumbent positions. Forced expiratory flow at 50% vital capacity (FEF50), forced inspiratory flow at 50% vital capacity (FIF50) and FEF50/FIF50 were determined. RESULTS: In the normal subjects FEF50, FIF50, and FEF50/FIF50 were not affected by change in posture or by breathing carbon dioxide. In the patients there was a fall in FIF50 and an increase in FEF50/FIF50 when breathing air in the supine position compared with values in the seated and lateral position. While they were breathing carbon dioxide there was a slight increase in FEF50 when patients were seated or in the lateral position compared with values during air breathing. Hypercapnia abolished the effects of posture on FEF50/FIF50. Values for FEF50/FIF50 in the supine position while they were breathing air correlated with the apnoeic index but not with other polysomnographic data. CONCLUSION: In patients with obstructive sleep apnoea the upper airway is prone to collapse during inspiration when the patient is supine, even when awake; this tendency can be reversed by breathing carbon dioxide.

To clarify the role of vagal afferents from the lung in the sensation of dyspnea, we examined the effects of prostaglandin E2 (PGE2) inhalation on the sensation of dyspnea during exercise in eight normal male subjects. This intervention was chosen because inhaled PGE2 is known to stimulate vagal afferent receptors in the lung, in particular C-fiber endings, without a significant increase in airway resistance. After either physiologic saline or PGE2 aerosol (100 micrograms/ml) inhalation through a Bird nebulizer for 2 min, exercise tests were performed on a bicycle ergometer. The tests consisted of 3 min at rest followed by graded work loads (zero to 150 watts, 50-watt increments). Minute ventilation (VE) and respiratory rate were monitored from an expiratory line through a face mask. Oxygen consumption (VO2) and carbon dioxide production (VCO2) were calculated from samples of mixed expired gas. The sensation of difficulty in breathing (dyspnea) was measured on a modified Borg scale at rest and at the end of each work load. We found that although airway resistance and lung volume did not change significantly between saline and PGE2 inhalations, inhaled PGE2 significantly increased the magnitude of the dyspneic sensation when compared with inhaled saline at the same levels of work load, ventilation, and oxygen consumption. These results suggest that in addition to probable roles of motor command and chemical drive, afferent vagal activity from the lung also contributes to the sensation of dyspnea during exercise.

The effect of sustained hypoxia on respiration is reported to be biphasic and comprised of an initial stimulatory phase mediated by peripheral chemoreceptors and a following depressive phase caused by central mechanisms (Neubauer, 1990). However, it is not clear how sustained hypoxia affects respiratory sensations. In this study we wished to ascertain whether sustained hypoxia has a biphasic effects on the sensation of dyspnea as well as on ventilation.

We previously reported that submental electrical stimulation may be an effective treatment for obstructive sleep apnea (Miki et al., 1989a, Hida et al., 1991). The mechanism of relief of apneic episodes during submental stimulation may be the contraction of genioglossus and/or geniohyoid muscles, which would open the upper airway by pulling the tongue forward (Miki et al, 1989b, Gottfried et al., 1983). However, the effects of submental stimulation during consecutive nights on apneic episodes in patients with obstructive sleep apnea (OSA) have not been studied. In the present study in order to assess whether submental stimulation is necessary for treatment every night, we examined the effects of submental stimulation for a serial four or five sleep nights on apneic episodes and changes in apneic episodes on stimulation-off nights after the stimulation nights using a portable submental stimulator which we have developed.

We assessed the effects of cooling the ventral medullary surface (VMS) on the activity of chest wall and abdominal expiratory muscles in eight anesthetized artificially ventilated dogs after vagotomy and denervation of the carotid sinus nerves. Electromyograms (EMGs) of the triangularis sterni, internal intercostal, abdominal external oblique, abdominal internal oblique, and transversus abdominis muscles were measured with EMG of the diaphragm as an index of inspiratory activity. Bilateral localized cooling (2 x 2 mm) in the thermosensitive intermediate part of the VMS produced temperature-dependent reduction in the EMG of diaphragm and abdominal muscles. The rib cage expiratory EMGs were little affected at 25 degrees C; their amplitudes decreased at lower VMS temperatures (less than 20 degrees C) but by significantly fewer degrees than the diaphragmatic and abdominal expiratory EMGs at a constant VMS temperature. With moderate to severe cooling (less than 20 degrees C) diaphragmatic EMG disappeared, but rib cage expiratory EMGs became tonic and resumed a phasic pattern shortly before the recovery of diaphragmatic EMG during rewarming of the VMS. These results indicate that the effects of cooling the VMS differ between the activity of rib cage and abdominal expiratory muscles. This variability may be due to inhomogeneous inputs from the VMS to expiratory motoneurons or to a different responsiveness of various expiratory motoneurons to the same input either from the VMS or the inspiratory neurons.

We assessed the effects of negative intrathoracic pressure induced by inspiratory elastic loading on pulmonary, gas exchange with and without electrically induced hindlimb exercise in 8 normal, anesthetized dogs. Two elastic loads (EL) were used; one of 81 and one of 140 cmH2O/liter. These are equivalent to doubling and tripling the normal elastance of the dog's respiratory system, respectively. Elastic loading decreased ventilation and caused hypoxemia and hypercapnia, but it did not affect systemic arterial pressure or heart rate. During exercise, increase in ventilation was limited, whereas increase in cardiac output was not affected by elastic loading. Alveolar-arterial O2 tension difference (A-aDO2) was not changed significantly by exercise alone. However, elastic loading accompanied by exercise increased A-aDO2. Although comparable end-inspiratory pleural pressure was achieved with large EL (-29 +/- 2 cmH2O, mean +/- SE) and small EL with exercise (-30 +/- 2 cmH2O), the latter increased A-aDO2 whereas the former did not. Large negative intrapleural pressure combined with increased cardiac output may have caused transient interstitial edema.

To elucidate the role of chemoresponsiveness in determining postapneic ventilation in sleep-disordered periodic breathing, we measured ventilatory response associated with apnea-induced arterial oxygen desaturation during sleep and compared it with the awake hypoxic ventilatory response (HVR) in 12 male patients with obstructive sleep apnea (OSA). Awake HVR was measured at a slight hypocapnic level (end-tidal PCO2 = 37 +/- 1 mm Hg, mean +/- SEM), and separately at a PCO2 of 45 mm Hg. During non-REM sleep both the ventilatory rate (VE) and the average respiratory frequency (f) in the ventilatory phase between apneic episodes were inversely correlated with the nadir of arterial oxygen saturation (nSaO2) produced by the preceding apneic phase in all patients (VE versus nSaO2; r = -0.74 +/- 0.03, mean +/- SEM; f versus nSaO2, r = -0.56 +/- 0.04). The average tidal volume (VT) also was correlated with nSaO2 in 10 of the patients (r = -0.56 +/- 0.05). During REM sleep VE was correlated with nSaO2 in 11 patients (r = -0.75 +/- 0.03, p less than 0.02). The response of VE to nSaO2 (delta VE/delta nSaO2) varied widely among the patients (non-REM, 0.52 to 2.16; REM, 0.29 to 1.44 L/min/%) and was significantly lower during REM than non-REM sleep (p less than 0.01). The value of delta VE/delta nSaO2 during both non-REM and REM sleep was correlated with awake HVR at an end-tidal PCO2 of 45 mm Hg (non-REM, r = 0.83, p less than 0.02; REM, r = 0.76, p less than 0.05) but not with that at the hypocapnic level.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to elucidate the mechanism of the bronchial response of monkeys to constrictive stimuli, the effects of pretreatment with aerosolized lidocaine, atropine, and isoproterenol were studied. Treatment with aerosolized lidocaine and atropine not only extinguished the cough reflex, but also decreased bronchial susceptibility to aerosolized methacholine. Moreover, the pretreatment with lidocaine blocked the histamine challenge, but atropine did not. The aerosolized lidocaine decreased the bronchoconstriction induced with methacholine, but not with histamine. Pretreatment with over 1% of isoproterenol did not extinguish the cough reflex. However, this dose of isoproterenol did suppress an increase in Rrs due to the challenge of both methacholine and histamine. Isoproterenol also decreased the bronchoconstriction due to the previous challenge by both methacholine and histamine. The antagonistic effects of lidocaine, atropine, and isoproterenol on the broncho-constriction of monkeys are discussed in relation to the subepithelial receptor.

We examined the relationship between response to hypercapnia and ventilatory response to exercise under graded anesthesia in eight dogs. The response to hypercapnia was measured by the CO2 rebreathing method under three grades of chloralose-urethan anesthesia. The degrees of response to hypercapnia (delta VE/delta PETCO2, 1 X min-1 X Torr-1) in light (L), moderate (M), and deep (D) anesthesia were 0.40 +/- 0.05 (mean +/- SE), 0.24 +/- 0.03, and 0.10 +/- 0.02, respectively, and were significantly different from each other. Under each grade of anesthesia, exercise was performed by electrically stimulating the bilateral femoral and sciatic nerves for 4 min. The time to reach 63% of full response of the increase in ventilation (tauVE) after beginning of exercise was 28.3 +/- 1.5, 38.1 +/- 5.2, and 56.0 +/- 6.1 s in L, M, and D, respectively. During steady-state exercise, minute ventilation (VE) in L, M, and D significantly increased to 6.17 +/- 0.39, 5.14 +/- 0.30, and 3.41 +/- 0.16 1 X min-1, from resting values of 3.93 +/- 0.34, 2.97 +/- 0.17, and 1.69 +/- 0.14 1 X min-1, respectively, while end-tidal CO2 tension (PETCO2) in L decreased significantly to 34.8 +/- 0.9 from 35.7 +/- 0.9, did not change in M (38.9 +/- 1.1 from 38.9 +/- 0.8), and increased significantly in D to 47.3 +/- 1.9 from 45.1 +/- 1.7 Torr.(ABSTRACT TRUNCATED AT 250 WORDS)

We examined airway responsiveness to allergen inhalation using a novel technique by which dynamic compliance (Cdyn) and pulmonary resistance (Rl) are simultaneously calculated by Fourier-series analysis of flow and transpulmonary pressure during tidal breathing. C0 and C0.5 (Cdyn at the frequency of zero and 0.5 Hz, respectively) were computed using the regression line of Cdyn versus frequency measured at the fundamental and first three harmonics in each breathing cycle. First, the validity of this system was tested by comparing Rl, C0 and C0.5 during five consecutive breaths with those obtained by the conventional method. A good correlation was seen in Rl, C0 and C0.5 between the two methods. Second, we studied airway response to allergen inhalation before and after oral administration of a long-acting β 2 -stimulant (procaterol, 50 μg or 100 μg) or placebo in a double-blind crossover trial in six atopic asthmatic subjects. In control allergen inhalation tests by administration of placebo, Rl increased progressively, and C0.5, expressed as percentage of control compliance at zero frequency (C0.5/C0cont), decreased progressively. After 100 μg procaterol, Rl response to allergen was almost completely inhibited. However, a decrease in C0.5/C0cont was still observed. These findings suggest that pretreatment of asthmatic patients with procaterol can release allergen-induced bronchoconstriction of the central airways, but cannot release that of the peripheral airways.