Search

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.

SHINDOH, C., HIDA, W., KUROSAWA, H., EBIHARA, S., KIKUCHI, Y., TAKISHIMA, T. and SHIRATO, K. Effects of Unilateral Phrenic Nerve Denervation on Diaphragm Contractility in Rat. Tohoku J. Exp. Med., 1994, 173 (3), 291-302- We examined the early effects of phrenic nerve denervation on the diaphragm muscle 1, 3, 7 and 14 days after unilateral denervation in rats. In the denervated hemidiaphragms, force frequency curves at 3, 7 and 14 days decreased significantly by 51%, 50% and 38% respectively of the peak tension of the force frequency curves of the diaphragms of rats with sham operation. Twitch tensions increased significantly at 14 days, and contraction times and half relaxation times slowed significantly at 3, 7 and 14 days. The tensions of denervated diaphragms at 5min during the fatigue runs was significantly increased at 14 days. As determined by histological staining, the mean cross sectional area of fast-twitch fibers (type II) decreased significantly from 2, 742 (sham) to 1, 599μm2 (14 days), but that of the slow-twitch fibers (type I) did not change significantly during the same period. These findings suggest that, during the first two weeks of denervation, fast twitch fibers (type II) atrophy more rapidly than slow twitch fatigue resistant fibers (type I), as confirmed by the contractile properties and histological findings.

Hypoxia causes a life-threatening situation, and the ventilatory response to hypoxia plays an important role in preventing death. We have hypothesized that persons with a blunted hypoxic ventilatory response may have a weak defense response to hypoxic episodes and be susceptible to fatal respiratory disturbances. However, precise correlations between the hypoxic ventilatory response and respiratory disturbances are not well understood. In the present study we examined the hypoxic and hypercapnic ventilatory responses in nine inbred mouse strains (A/J, AKR/N, BALB/c, C3H/He, C57BL/6, DBA/2, NZW, SWR/J, and 129Sv). Breathing frequency, tidal volume and minute ventilation of unanesthetized and unrestrained mice were assessed by whole body plethysmography. Age-matched mice were exposed for 3 min to 10% O(2) in N(2) gas or 10% CO(2) in hyperoxic gas to determine the acute ventilatory response to chemical stimuli. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the highest in AKR/N mice and the lowest in SWR/J mice. These findings suggest that genetic factors may have influenced the hypoxic ventilatory response but not the hypercapnic ventilatory response. To examine the effects of severe hypoxic stress on the respiratory cycle, we exposed the strain with the highest or lowest hypoxic ventilatory response to 6% O(2) in N(2) until the onset of apnea. The "appearance time of apnea", which is defined as the time from the hypoxic loading to the onset of apnea, was shorter in the SWR/J strain than in the AKR/N strain. We suggest that a lower hypoxic ventilatory response may be a risk factor for apnea under hypoxia.

In Japan, spirometry has not been included as an item in medical check-ups for all persons. The purpose of this study was to show evidence to recommend spirometry routinely on medical check-up for the early detection of chronic obstructive pulmonary disease (COPD). There were 12,760 enrolled persons who underwent medical check-up. COPD was defined as a ratio of forced expiratory volume in one second to slow vital capacity of 70% or less. We investigated the prevalence and its characteristics of COPD in people on medical check-up. The prevalence of COPD was 3.6% in all subjects, 4.5% in males, and 1.8% in females. In the comparison between males and females, the prevalence of COPD in males of most age groups was higher than that of females, and this difference was greater with aging. Males in their 50s and over 60 years old and females over 60 years old showed remarkably high prevalences. Occupations associated with a high smoking rate such as transportation-related occupations showed a higher prevalence of COPD. These results suggest that spirometry for all persons in medical check-ups can identify many COPD patients not aware of this disease. Spirometry should be carried out routinely on medical check-up.

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 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 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.

IZUMIYAMA, T., HIDA, W., ICHINOSE, M., INOUE, H., TAKISHIMA, T., OKAZAKI, T. and SHIRATO, K. Small Airway Involvement in Mixed Connective Tissue Disease. Tohoku J. Exp. Med., 1993, 170 (4), 273-283-We studied pulmonary functions in 17 female patients with mixed connective tissue disease (MCTD) to detect early pulmonary involvement in this disease; in 8 of the 17 patients follow-up studies were also performed at 1.2- to 5.9-year intervals. In the first pulmonary function tests, decreases in vital capacity (VC) and diffusing capacity (DLCO) were observed in 6 (35%) and 8 (47%) patients, respectively. The ratio of forced expiratory volume in one second to VC was normal in all the patients, but pulmonary resistance and static compliance were abnormal in 6 (35%) and 10 (59%) patients, respectively. However, frequency dependence of dynamic compliance was found in all 16 patients tested. Moreover, 4 (24%) of the 17 patients had normal DLCO and DLCO-to-alveolar volume ratio (DLCO/VA). Reductions in DLCO and DLCO/VA were significantly correlated with the disease duration. These results suggest that small airway obstruction is an early and frequent indication of functional pulmonary impairment, and that impairment of alveolar gas exchange is progressive in patients with MCTD.

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.

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 studied bronchial responsiveness to methacholine in 10 normal subjects, in 60 patients with bronchial asthma and in 30 patients with bronchitis using a new device, with which we were able to obtain the dose-response curve of respiratory resistance (Rrs) continuously and graphically by the 3 Hz oscillation method during inhalation of methacholine. All normal subjects were non-responders, while all of the bronchial asthma cases, 63% of the chronic bronchitis cases and 50% of the acute bronchitis cases were responders. Among responders we found a very poor correlation between the initial respiratory conductance (Grs.cont) and the bronchial sensitivity (defined as the reverse of the cumulative dose until Rrs starts to increase); yet we found a good correlation between Grs.cont and the bronchial reactivity (defined as the slope of the decreasing rate of Grs). Metaproterenol and atropine decreased the bronchial sensitivity and reactivity in 28 asthmatic patients. We concluded that for clinical purposes the new method was very useful for assessing bronchial responsiveness to inhalation challenge because of its simplicity of operation as well as the quantitative differentiation between bronchial sensitivity and reactivity. Our results suggest that the bronchial response system to methacholine is explainable by a model of multiple dose-response curves without any parallel shift.

In 8 healthy subjects (group A) and 4 subjects with respiratory symptoms (group B), the lung pressure-volume curve (P-V curve), maximum expiratory flow-volume curve (MEFVC) and respiratory resistance (Rrs) at all vital capacities were measured. To avoid laryngeal artifact on a mouth pressure, an intratracheal catheter was used for measurement of Rrs which was obtained with 3 cycles/sec oscillatory forced pressure. Group B did not show a different elastic recoil from group A. In comparison of the maximum expiratory flow (Vmax) at 80, 70, 60 and 50% of the total lung capacity (TLC). Vmax of group B showed lower values than that of group A. Rrs was almost the same in both groups from 70% TLC upwards, but Rrs of group B was higher than that of group A from 65%TLC downwards. Since the lung elastic recoil pressures (Pst (1)) in the two groups were not different and Rrs's were different significantly only at low lung volumes, the decrease in Vmax of group B was supposed to be due to the increased Rrs which might reflect small airway obstruction.

MIKI, H., HIDA, W., SHINDOH, C., TAGUCHI, O., INOUE, H. and TAKISHIMA, T. Effect of Electrical Stimulation of Genioglossus Muscle on Upper Airway Resistance in Anesthetized Dogs. Tohoku J. exp. Med., 1987, 153 (4), 397-398 - The isolated upper airway pressure and flow changes during electrical stimulation of the genioglossus muscle in spontaneously breathing anesthetized dogs were measured at given pressures in the inspiratory direction. Upper airway resistance was maximal during no stimulation and decreased rapidly with stimulation at frequencies up to about 40Hz.

In order to examine the effect of sleep position on sleep apnea episodes, seven male patients diagnosed as having obstructive sleep apnea syndrome without any organic complication of the upper airway were studied while lying in a supine or lateral position during an all-night polysomnographic study. Apnea index, apnea time/total sleep time (%) and the number of episodes per hour in which oxyhemoglobin saturation dropped below 85% decreased significantly from 51.0 +/- 8.6 (mean +/- S.D.) events/hr, 40.4 +/- 5.8% and 36.2 +/- 9.8 episodes/hr during sleep in supine position to 27.6 +/- 9.1 events/hr, 19.4 +/- 6.0% and 12.9 +/- 5.3 episodes/hr during sleep in lateral position, respectively. Lowest oxyhemoglobin saturation increased significantly from 70.7 +/- 2.6% to 78.0 +/- 2.4%. Thus, sleep in the lateral position may be a simple treatment before essential treatment for patients with obstructive sleep apnea syndrome.

We have developed a portable home sleep monitoring system using nasal airflow (NA), tracheal sound recordings (TSR), and electrocardiogram (ECG). NA was recorded by two thermisters. TSR was recorded by a microphone attached to the skin overlying the cervical trachea. Three kinds of signals were recorded with a cassette recorder. Thirty-seven outpatients who had sleep complaints were monitored during sleep at home using this recorder. Attachment of the pickups was performed by the patients themselves. Recordings were played back and analyzed by a personal computer to evaluate apnea episodes from TSR and R-R intervals beat by beat. This home monitoring system had labor-saving and cost-saving benefits and seemed to be a satisfactory technique for screening.

To examine whether or not the respiratory muscle weakness is correlated with decrease in arterial oxygen tension (PaO2), respiratory muscle and pulmonary functions in 14 patients with neuromuscular diseases (NMD) were studied and compared with those of 12 patients with chronic pulmonary emphysema (CPE) and 15 patients with idiopathic pulmonary fibrosis (IPF). Respiratory muscle strength was assessed by maximal static inspiratory and expiratory mouth pressure at three lung volumes (RV, FRC and TLC). Although mean pulmonary functions in NMD showed virtually normal function, respiratory muscle strength was significantly less than the corresponding values in CPE and IPF. In NMD, maximal inspiratory mouth pressure at RV level (PImax) correlated positively with %TLC and %VC (r = 0.652 and r = 0.536, respectively). Moreover, PImax was significantly correlated with PaO2 (r = 0.561), but not with PaCO2. Maximal expiratory mouth pressure at TLC (PEmax) correlated positively with %TLC and %VC. In CPE and IPF, respiratory muscle strength had no correlation with PaO2 and PaCO2. These findings suggest that inspiratory muscle dysfunction in NMD may be one of the factors responsible for determination of the level of hypoxemia and lung volume.

MUE, S., OHMI, T., SUZUKI, S., TAMURA, G., HIDA, W., SEKIZAWA, K., ISHIHARA, T., YAMAUCHI, K. and TAKISHIMA, T. The Effect of Adrenergic and Cholinergic Drugs on Methacholine- and Histamine-Induced Bronchoconstriction in Monkeys. Tohoku J. exp. Med., 1983, 140 (2), 109-119 - The effect of adrenergic and cholinergic drugs on bronchial contraction of monkeys was studied using bronchoconstriction induced by aerosol challenge with methacholine and histamine. Under the anesthesia with ketamine hydrochloride, changes in the total respiratory resistance were continuously measured in monkeys to estimate the bronchial response to both histamine and methacholine. Isoprenaline decreased bronchial susceptibility to aerosol challenge with both methacholine and histamine. Isoprenaline was also potent in antagonizing the bronchoconstriction induced by methacholine and histamine. Atropine decreased bronchial susceptibility to aerosol challenge with methacholine and also partially with histamine. Atropine also antagonized the bronchoconstriction induced by methacholine, but not by histamine. Phentolamine had neither inhibitory effects on the aerosol challenge with methacholine and histamine, nor produced an antagonistic effect on bronchoconstriction induced with methacholine and histamine.

HIDA, W., TAGUCHI, O., IWASE, N., SATO, M., CHONAN, T., KIKUCHI, Y., OGATA, M., SHIRATO, K. and TAKISHIMA, T. Change in P Wave Height during Progressive Exercise in Patients with Chronic Obstructive Pulmonary Disease. Tohoku J. Exp. Med., 1989, 157 (1) 79-80 - We examined changes in P wave height in lead II of electrocardiogram during progressive exercise in patients with chronic obstructive pulmonary disease (COPD), and obtained the slope (ΔP/ΔVO2, %/ml/min) of the regression line calculated from the relationship between percent change of P wave height and oxygen consumption (VO2). Four COPD patients, who had a decrease over 5mmHg in arterial oxygen tension (PaO2) at maximal exercise (group A), had significantly greater slope (0.45±0.14%/ml/min, mean±S.E.) than in five COPD patients (group B, 0.14±0.05), who did not have a decrease over 5mmHg in PaO2 at maximal exercise. The increase in P wave height during exercise was inhibited by oxygen inhalation at the given VO2 in group A. These findings suggest that increase in P wave height during exercise in COPD patients may be correlated with hypoxemia during exercise.

MIKI, H., HIDA, W., INOUE, H. and TAKISHIMA, T. A New Treatment for Obstructive Sleep Apnea Syndrome by Electrical Stimulation of Submental Region. Tohoku J. exp. Med., 1988, 154 (1), 91-92 - Loss of upper airway muscle tone during sleep has been thought to be responsible for obstructive apnea episodes. To examine the effect of electrical stimulation of the submental region on sleep apnea episodes, patients with obstructive sleep apnea syndrome were polysomnographically studied during all-night session with and without stimulation.