[Pulmonary hypertension].

Repetitive pulmonary artery pressure(PAP) elevation during apnea is commonly reported in patients with obstructive sleep apnea syndrome(OSAS). Hypoxic pulmonary vasoconstriction(HPV) plays an important role in this PAP elevation. In addition to the HPV, augmentation of intrathoracic negative pressure which occurs concomitantly with apnea and activation of sympathetic nervous system during REM sleep, influences pulmonary blood flow, resulting in the PAP elevation. Many previous study have been declared that the daytime pulmonary hypertension(PH), which is observed in significant populations of OSAS, is related to chronic airflow limitation and/or daytime hypoxemia. Furthermore, it had been suggested that the daytime PH in OSAS can be elicited, at least in parts, by vascular remodeling together with both nocturnal and daytime hypoxemia. Such pulmonary vascular remodeling may induce greater vascular sensitivity to sympathetic stimulation and modify HPV in OSAS with daytime PH.

Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome.

The effect of sleep stage change on pulmonary circulation has not been well documented in patients with obstructive sleep apnea syndrome (OSAS). We investigated whether or not stage-specific change can affect pulmonary artery pressure (Ppa) in patients with OSAS. Thirty-one patients with OSAS underwent right cardiac catheterization in the daytime and the following night, including 19 patients in whom Ppa could be measured throughout non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Ten of the 19 patients had daytime pulmonary hypertension (PH) defined by a mean Ppa (Ppa) >/= 20 mm Hg. Then we analyzed Ppa response to hypoxia spontaneously occurring during the period of sleep apnea. The slopes of the regression lines between arterial oxygen saturation measured by pulse oximeter (SpO2) and Ppa curves were almost the same in both NREM and REM patient groups with or without daytime PH, whereas the response curve was significantly shifted upward in REM compared with NREM patients with daytime PH. Furthermore, Ppa was elevated more markedly in association with REM burst, phasic REM, compared with tonic REM. We conclude that vascular tone of pulmonary artery could be elevated in association with REM sleep which is independent of the degree of hypoxia, and that this state-specific change is manifested in patients with daytime PH.

A new aspect of the carotid body function controlling hypoxic ventilatory decline in humans.

Ventilatory response to eucapnic sustained mild hypoxia was measured in one patient with unilateral and three patients with bilateral carotid body (CB) resection (defined UR and BR, respectively). The profile of ventilatory response in UR patient was initially augmented then gradually declined (biphasic pattern) as generally seen in normal subjects although the absolute magnitude was substantially low. On the other hand, biphasic pattern was disappeared in all three BRs. Lack of hypoxic ventilatory decline (HVD) in the late period of sustained hypoxia was in marked contrast to that reported in the anaesthetized and CB-denervated animals whose ventilation was severely depressed lower than the pre-hypoxic control level. In view of recent knowledge that the analogous mild hypoxia in normal animals and humans elicits an useful adaptation to economize energy expenditure with maintaining reversible excitability in control of respiration, BR patients were considered to have lost this ability. We conclude that in awake humans the CB not only stimulates ventilation but also controls the degree of subsequent HVD during sustained hypoxia.

Effects of chest wall vibration on breathlessness during hypercapnic ventilatory response.

Vibratory stimulation applied to the chest wall during inspiration reduces the intensity of breathlessness, whereas the same stimulation during expiration has no effect or may increase breathlessness. The purpose of the present study was to determine whether vibration reduced the intensity of breathlessness during progressive hypercapnia with and without the addition of an external resistive load. A second objective was to see whether the mouth occlusion pressure at 0.2 s (P0.2) was reduced by the vibratory stimulation. Hypercapnic ventilatory response was conducted in 10 healthy male volunteers with simultaneous measurement of visual analog scale, P0.2, and minute ventilation. Hypercapnic ventilatory response was performed and randomly combined with or without vibratory stimulation (100 Hz) as well as with or without inspiratory load. With inspiratory load, in-phase vibration did not cause any significant changes in the slopes of P0.2 and minute ventilation to CO2, whereas the slope of visual analog scale to CO2 significantly decreased from 0.47 +/- 0.15 to 0.34 +/- 0.11 (SE) cm/Torr (P < 0.05). We conclude that in-phase vibration could decrease the slope of breathlessness elicited by inspiratory load combined with hypercapnia without changing motor output.

Compensatory excretion of prostacyclin and thromboxane metabolites in obstructive sleep apnea syndrome.

Since obstructive sleep apnea syndrome (OSAS) is often linked with systemic hypertension, we sought to clarify the characteristics of prostanoid metabolism in OSAS. In 7 OSAS patients (apnea-hypopnea index, 51.0 +/- 23.4) and 7 non-snorers as control, nocturnal urine was sampled and analyzed for stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), [6-keto-PGF1alpha and thromboxane B2 (TxB2)]. The ratio of 6-keto-PGF1alpha to TxB2 was significantly higher in OSAS (2.97 +/- 1.52) than in control (1.38 +/- 0.38). Successful treatment with nasal continuous positive airway pressure (8.3 +/- 1.5 cmH2O) for 3 days caused a significant decrease in mean blood pressure in OSAS. Moreover, the 6-keto-PGF1alpha to TxB2 ratio also significantly decreased to 1.74 +/- 0.58, a level which may not significantly different from control. These results suggest that the production ratio of PGI2 to TxA2 is shifted toward vasodilatation in untreated OSAS. We conclude that the production of prostanoids plays a role in compensating for the systemic hypertension in OSAS.

Control of upper airway function in response to hypoxia in patients with obstructive sleep apnea syndrome.

To clarify the characteristics of upper airway muscles under hypoxic condition in obstructive sleep apnea syndrome (OSAS), we performed the isocapnic progressive hypoxia test during wakefulness in 8 controls and 7 OSAS patients. Electromyographic activities were recorded from the genioglossal muscle (EMG(GG)) and diaphragm (EMG(DIA)) with ventilatory variables. Minute EMG (peak integrated EMG x respiratory rate) activity against P(ET)O2 was calculated by exponential equation, and its response slope represented the hypoxic sensitivity of each muscle, slope(GG) and slope(DIA). There was no significant difference between the slopes of OSAS and control. In contrast, the ratio of the two responses, slope(GG)/slope(DIA), was significantly higher in OSAS (1.61 +/- 0.49 SD) than in control (0.98 +/- 0.43). Moreover, the slope(GG)/slope(DIA) ratio was negatively correlated with the ratio of sleep time with SpO2 lower than 90% to total sleep time. We conclude that the neuromuscular compensatory mechanism of upper airway muscles is effectively developed and plays an important role in preventing nocturnal hypoxemia in OSAS.

Free synovium promotes meniscal healing. Synovium, muscle and synthetic mesh compared in dogs.

We studied the effect of free synovium on the healing of tears in the avascular portion of the menisci in dogs. A longitudinal incision was made in the medial meniscus. In 35 dogs, a free graft of synovium was inserted into the tear and sutured. In 10 dogs, a free graft of quadriceps muscle was used. In 10 dogs, a Dacron mesh was inserted. In the contralateral knee, the tear was sutured without implantation as a control. 2, 4, 6, 8, and 12 weeks after the operation, the menisci were dissected. 11 of the 35 with free synovium were healed. The menisci with muscle grafts, those with Dacron mesh and those in the control group did not heal. Histology showed that tears were repaired with fibrous tissue. Microangiography showed that capillaries grew from the periphery, but they did not reach the tear.

[Nocturnal pulmonary hypertension in patients with obstructive sleep apnea associated with daytime pulmonary hypertension].

We investigated the effect of state-specific changes associated with REM sleep on pulmonary artery pressure in patients with obstructive sleep apnea (OSAS). Six male patients with OSAS (age; 40 +/- 12 SD yrs, BMI; 39.0 +/- 8.6 kg/m2, AHI; 51.5 +/- 28.5) were examined throughout the night by polysomnography, while monitoring pulmonary artery pressure via right cardiac catheterization. All patients had pulmonary hypertension (PH) during periods of wakefulness, and their mean pulmonary artery pressure (PAPm) was 31.1 +/- 7.4 mmHg. PAPm was analyzed at two different points in each apneic episode. PAPbase was the baseline value when inspiratory effects during apnea were not elicited, and PAPpeak was the peak value observed just after the cessation of OSA. PAPpeak was higher in REM (56.3 +/- 12.4) than in NREM (41.4 +/- 6.9 mmHg; P < 0.01), and both values were significantly higher than those observed during periods of wakefulness. The magnitude of elevation of PAP (delta PAP; PAPpeak-PAPbase) in REM and NREM were 11.6 +/- 2.0 and 6.9 +/- 2.8 mmHg, respectively. Relative ratios in the response of PAP to a decrease in O2 desaturation (delta PAP/delta SpO2) showed almost the same value for REM (-0.57 +/- 0.27) and NREM sleep (-0.57 +/- 0.26 mmHg/%). The values of PAPm at SpO2 75% were significantly higher in REM than in NREM (48.7 +/- 11.2 vs. 41.6 +/- 6.2 mmHg). We conclude that transient pulmonary hypertension could be caused not only by hypoxia, but also by state-specific responses (which are unrelated to hypoxia) that occur during REM sleep.

Second look arthroscopy after meniscal repair. Factors affecting the healing rate.

Second look arthroscopy was performed on 46 of 137 consecutive patients who underwent arthroscopic meniscal repair. All tears were of the vertical type. Thirty-two tears were located in avascularized areas. Thirty-one patients had associated anterior cruciate ligament insufficiencies. Anterior cruciate ligament reconstructions were performed simultaneously on 26 patients. The double-needle cannula method was used in all the patients. An additional transplantation of a vascularized synovial pedicle flap to the suture site was performed on 7 tears in avascularized areas. Second look arthroscopy showed no healing in 8 patients and healing in 38. Four of the 8 unhealed tears were located in avascularized areas, and 4 had unreconstructed anterior cruciate ligament injuries respectively. All 7 patients with synovial pedicle flaps showed healing. All patients with anterior cruciate ligament reconstructions showed healing, and the healing rate was significantly higher than that of the other patients (p < 0.005). Patients with anterior cruciate ligament insufficiencies showed a significantly lower healing rate than the others (p < 0.005). In patients with tears in avascularized areas, the conventional meniscal repairs showed a lower healing rate than did the repairs with a synovial pedicle transplantation or an anterior cruciate ligament reconstruction (p < 0.005). These results suggest that the most important factors influencing meniscal healing are the presence of anterior cruciate ligament tears, ligamentous reconstruction, and vascularity of the tear site.

Meniscal repair using a flap of synovium. An experimental study in the dog.

The healing process of longitudinal lesions in the avascular region of the meniscus was investigated in 42 menisci from 21 dogs. A longitudinal incision was made in the avascular portion of the medial menisci of 21 dogs. In one knee, a flap of synovium was sutured into the wound, and in the other, the wound was sutured as a control. Animals were killed after 1 to 12 weeks, and the menisci were removed and examined by gross inspection, light microscopy, and microangiography. In the control knees, no healing had occurred. In 19 of 21 knees in which a synovial pedicle was used, the suture site did not open at any of the postoperative weeks. The longitudinal lesion was repaired with fibrovascular tissue at 6 weeks, and the vessels over the femoral surface of the menisci and an inner portion of the menisci had reached the suture site. The healing of meniscal lesion occurred due to the use of the vascularized synovial pedicle flap and the neovascularization from the parameniscal area.

Differences in the response of genioglossal muscle activity to sustained hypoxia between healthy subjects and patients with obstructive sleep apnea.

The depression of EMG activity in upper airway muscles during sleep is known to be a predisposing factor causing upper airway obstruction in patients with obstructive sleep apnea syndrome (OSAS). To clarify whether or not the selective depression of upper airway muscles could be associated with the hypoxic ventilatory depression, we performed sustained hypercapnic hypoxia tests during wakefulness in 11 control subjects and 10 patients with OSAS. Isocapnic sustained hypoxia around SaO2 80% with mild hypercapnia [PETO2: 45.8 +/- 1.6 (SD) and 46.7 +/- 2.8 mm Hg and PETCO2: 44.2 +/- 4.7 and 43.1 +/- 5.0 mm Hg in control and OSAS groups, respectively] was applied for 20 min. Electromyogram activities were recorded from the genioglossal muscle (EMGGG) and diaphragm (EMGDIA) with ventilatory variables. The magnitudes of hypoxic depression in terms of minute ventilation (VI) and minute EMGDIA (EMGDIA/min) were compared in percentage between peak value and the value at the late period. These values were not significantly different between two groups (VI: 79.2 +/- 10.7 and 66.9 +/- 12.8% and EMGDIA/min: 63.2 +/- 17.1 and 60.4 +/- 24.0% in control and OSAS, respectively). On the contrary, the depression in EMGGG was not consistently observed in control (86.1 +/- 38.6% of the peak value) whereas EMGGG was markedly depressed in OSAS (38.6 +/- 15.7% of the peak value; p < 0.01). It is concluded that sustained hypoxia attenuates the activity in genioglossal muscle in patients with OSAS, but not in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of hypoxic depression on genioglossal muscle activity in healthy subjects and obstructive sleep apnea patients.

We investigated whether selective depression of the genioglossus muscle (GG) activity could be associated with hypoxic ventilatory depression, which is developed in the late phase of the biphasic ventilatory response during sustained hypoxia. Eleven control subjects and 10 patients with obstructive sleep apnea syndrome (OSAS) were examined by an isocapnic sustained hypoxia test for 20 minutes. Ventilatory parameters and electromyographic (EMG) activities were recorded from GG (EMGGG) and diaphragm (EMGDIA). Hypoxic depression in minute ventilation (V1) and EMGDIA occurred when compared between the peak value and the value at late period in both groups. On the contrary, depression in EMGGG was not observed in controls (86% of the peak value), whereas EMGGG was strikingly depressed in OSAS (39% of the peak value). We conclude that sustained hypoxia reduces the activity of GG in OSAS, but not in control subjects. These data suggest that the lack of a compensatory response of GG to sustained hypoxia is possibly responsible for the pathogenesis of OSA.

[Epidemiological study of snoring--a questionnaire survey in factory workers].

There has been no epidemiological study of snoring in Japan, and we therefore performed a questionnaire survey (in about 7,000 adult men working at a steel-making factory at the time of the yearly health examination, and investigated the relationship between the severity of snoring and 17 items including age, obesity, family history of snoring, daytime hypersomnolence, hypertension, smoking, alcohol intake and traffic accidents. We classified all the subjects into three groups, no snoring, mild snoring, and severe snoring group. We defined severe snorers as persons who snored loudly in both inspiratory and expiratory phases and those who snored loudly with apnea. We found that aging, obesity, smoking and alcohol intake are risk factors for snoring. Compared with non-snorers, severe snorers were found to have a high incidence of family history of snoring, daytime hypersomnolence, and history of treatment of hypertension. No relationship was found between the severity of snoring and the occurrence of automobile accidents. The proportion of severe snorers over 40 years old with obesity, daytime hypersomnolence and morning headache was 0.25%, representing the group that may have obstructive sleep apnea syndrome. The probable incidence of sleep apnea syndrome in men may be considerably lower in Japan compared with that in either U.S.A. or Europe.

[Hypoxic ventilatory response and hypoxic depression].

We investigated whether or not the adaptation of peripheral chemoreceptor (PCR) activity can contribute to hypoxic ventilatory depression (HVD) during sustained hypoxia for 20 min in both healthy subjects and patients with sleep apnea. Effects of HVD on diaphragm (DIA) and genioglossal muscle (GG) were also assessed. Withdrawal test, which is well established to solely represent the function of PCR, was repeatedly conducted at 5 and 20 min during sustained hypoxic condition. The results suggested that PCR did not play an important role in the development of HVD. When HVD ensued during sustained hypoxia, minute ventilation and EMGDIA were suppressed to the same extent in both groups. On the other hand, EMGGG was strongly and consistently attenuated in OSAS, whereas it was not always the case in healthy subjects. We speculate that treatment for hypoxic conditions can induce improvement of impaired regulation of breathing via central mechanisms, and it can be an important factor reducing the incidence and the severity of upper airway occlusion or collapse.

[Improvement of respiratory function with weight reduction in obese elderly].

The patient was a 74-year-old woman who had been obese since age 18. Her obesity was refractory to dietary manipulation. She had been suffering from increasing dyspnea for several months and eventually could not even move. She was admitted to a hospital and diagnosed as having heart failure. Although her cardiac function recovered with medical treatment, her symptoms did not improve. The patient was then sent to our hospital. On admission, her height and weight were 149 cm and 81.9 kg, respectively, yielding a body mass index (BMI) of 36.6 kg/m2. Arterial blood gas analysis in room air revealed hypoxemia and an apnea index of 27 per hour. She was given a daily 500-1000 kcal diet. After four months of treatment, her weight decreased to 65 kg with a BMI of 29.3 kg/m2. Weight reduction together with the usage of progesterone-derivatives resulted in marked improvement of sleep apnea. The apnea index decreased to 3/h and arterial blood gas values normalized. This patient seemed to have suffered from both obesity hypoventilation syndrome and sleep apnea syndrome. Improvement of respiratory function was achieved through relief of airway obstruction and weight reduction, with activation of the respiratory center due to progesterone treatment.