Familial 'sleep apnea plus' syndrome: report of a family.

We describe a familial disorder consisting of sleep apnea, anosmia, colorblindness, partial complex seizures, and cognitive dysfunction. The phenotypic expression of the syndrome suggests an autosomal dominant inheritance with incomplete penetrance.

Long-term effects of almitrine bismesylate on oxygenation during wakefulness and sleep in chronic obstructive pulmonary disease.

Hypoxemia in patients with chronic obstructive pulmonary disease (COPD) becomes more pronounced during sleep and can result in a number of serious consequences. Almitrine bismesylate is a peripheral chemoreceptor agonist that improves arterial oxygen tension (PaO2) in patients with COPD during wakefulness. Studies conducted for up to six months suggested the agonist may be useful in the management of nocturnal hypoxemia. In this double-blind, parallel, placebo-controlled study, patients with COPD received 50 mg of almitrine bismesylate (n = 9) or placebo (n = 11) twice a day for one year. Almitrine bismesylate increased PaO2 by 8.1 +/- 2.1 mm Hg (mean +/- SEM), decreased arterial carbon dioxide tension by 3.0 +/- 0.7 mm Hg (mean +/- SEM), and increased minute ventilation by 3.1 +/- 0.5 liters/minute (mean +/- SEM) during wakefulness. All of these changes were statistically significant. Five patients in the almitrine bismesylate group and eight patients in the placebo group completed sleep studies prior to and after 56, 180, and 360 days of almitrine bismesylate or placebo administration. Relative to placebo, almitrine bismesylate significantly increased oxygen saturation during sleep without any significant changes in the quantity or quality of sleep.

Effect of hypoxia on ventilatory and arousal responses to CO2 during NREM sleep with and without flurazepam in young adults.

We examined the ventilatory response to CO2 at two levels of oxygenation during wakefulness and sleep in healthy young adults before and after the ingestion of a single dose of 30 mg flurazepam. Progressive hypercapnia was produced at two levels of arterial O2 saturation (greater than 99 and 87%) by having subjects re-breathe from a tight-fitting face mask and a reservoir bag containing gas mixtures with two different O2 concentrations. Ventilation was measured with an inductive plethysmograph. O2 saturation was measured with an ear oximeter. Sleep was monitored using standard techniques by recording the electroencephalogram, eye movements, and chin electromyogram. During wakefulness, hypoxia increased the slope of the ventilatory response to CO2 and shifted the response slightly to the left. NREM sleep lowered the slope of the CO2 response under both hyperoxic and hypoxic conditions. The slope of the hyperoxic CO2 response curve was not affected by flurazepam during wakefulness or sleep. After administration of flurazepam to the subjects, the shift of the CO2 response curve to the left produced by hypoxia (additive effect) during NREM sleep was slightly less as compared to control, but hypoxia still increased the slope of the CO2 ventilatory response. During hypoxic hypercapnia, the PCO2 at arousal from sleep was significantly lower than during hyperoxic hypercapnia, but the level of ventilation at arousal during hypercapnia was similar in the control condition and after flurazepam. We conclude that (a) both natural and flurazepam-induced sleep depress ventilatory responses to hyperoxic and hypoxic hypercapnia and alter, in a complex fashion, the effects of hypoxia and hypercapnia on ventilation; and (b) hypoxia and hypercapnia interact as arousal stimuli in both natural and flurazepam-induced sleep.

Nicotine: a different approach to treatment of obstructive sleep apnea.

Reduced upper airway muscle activity may contribute to the occurrence of obstructive apneas during sleep. There is no uniformly successful treatment of these apneas, and it is possible that agents which increase upper airway muscle activity could reduce the occurrence of obstruction during sleep. Nicotine, a known stimulant of breathing, also increases the activity of muscles which dilate the upper airway proportionally more than it does ventilation. Hence, we evaluated the effect of nicotine on apneas during the first two hours of sleep in eight patients with sleep apnea syndrome. It was concluded that nicotine reduces apneas during the early hours of sleep, and this effect may be caused by its stimulating action on upper airway muscles.

Nonrandom variability in respiratory cycle parameters of humans during stage 2 sleep.

We analyzed breath-to-breath inspiratory time (TI), expiratory time (TE), inspiratory volume (VI), and minute ventilation (Vm) from 11 normal subjects during stage 2 sleep. The analysis consisted of 1) fitting first- and second-order autoregressive models (AR1 and AR2) and 2) obtaining the power spectra of the data by fast-Fourier transform. For the AR2 model, the only coefficients that were statistically different from zero were the average alpha 1 (a1) for TI, VI, and Vm (a1 = 0.19, 0.29, and 0.15, respectively). However, the power spectra of all parameters often exhibited peaks at low frequency (less than 0.2 cycles/breath) and/or at high frequency (greater than 0.2 cycles/breath), indicative of periodic oscillations. After accounting for the corrupting effects of added oscillations on the a1 estimates, we conclude that 1) breath-to-breath fluctuations of VI, and to a lesser extent TI and Vm, exhibit a first-order autoregressive structure such that fluctuations of each breath are positively correlated with those of immediately preceding breaths and 2) the correlated components of variability in TE are mostly due to discrete high- and/or low-frequency oscillations with no underlying autoregressive structure. We propose that the autoregressive structure of VI, TI, and Vm during spontaneous breathing in stage 2 sleep may reflect either a central neural mechanism or the effects of noise in respiratory chemical feedback loops; the presence of low-frequency oscillations, seen more often in Vm, suggests possible instability in the chemical feedback loops. Mechanisms of high-frequency periodicities, seen more often in TE, are unknown.

Possible mechanisms of periodic breathing during sleep.

To determine the effect of respiratory control system loop gain on periodic breathing during sleep, 10 volunteers were studied during stage 1-2 non-rapid-eye-movement (NREM) sleep while breathing room air (room air control), while hypoxic (hypoxia control), and while wearing a tight-fitting mask that augmented control system gain by mechanically increasing the effect of ventilation on arterial O2 saturation (SaO2) (hypoxia increased gain). Ventilatory responses to progressive hypoxia at two steady-state end-tidal PCO2 levels and to progressive hypercapnia at two levels of oxygenation were measured during wakefulness as indexes of controller gain. Under increased gain conditions, five male subjects developed periodic breathing with recurrent cycles of hyperventilation and apnea; the remaining subjects had nonperiodic patterns of hyperventilation. Periodic breathers had greater ventilatory response slopes to hypercapnia under either hyperoxic or hypoxic conditions than nonperiodic breathers (2.98 +/- 0.72 vs. 1.50 +/- 0.39 l.min-1.Torr-1; 4.39 +/- 2.05 vs. 1.72 +/- 0.86 l.min-1.Torr-1; for both, P less than 0.04) and greater ventilatory responsiveness to hypoxia at a PCO2 of 46.5 Torr (2.07 +/- 0.91 vs. 0.87 +/- 0.38 l.min-1.% fall in SaO2(-1); P less than 0.04). To assess whether spontaneous oscillations in ventilation contributed to periodic breathing, power spectrum analysis was used to detect significant cyclic patterns in ventilation during NREM sleep. Oscillations occurred more frequently in periodic breathers, and hypercapnic responses were higher in subjects with oscillations than those without. The results suggest that spontaneous oscillations in ventilation are common during sleep and can be converted to periodic breathing with apnea when loop gain is increased.

Respiratory and hematological adaptations of young and older Aymara men native to 3600M.

This paper reports the results of a study designed to test the hypothesis that an inevitable concomitant of aging at high altitudes is chronic mountain sickness resulting from excess erythrocytosis secondary to exaggerated hypoxemia caused by aging processes in the respiratory system. It compares age differences in respiratory system function in oxygenating the blood measured as percent O2 saturation of arterial hemoglobin during wakefulness and sleep and in erythrocytosis measured as hemoglobin concentration in 17 young (22-35 years) and 16 older (47-68 years) rural and urban resident Bolivian Aymara men, healthy lifelong residents of 3,500-4,000 m who were tested at 3,600 m. The results do not support the hypothesis. Older urban men are significantly more hypoxemic during wakefulness and sleep than young urban men, while there are no age differences in the degree of hypoxemia among the rural residents. However, older urban men do not have the higher hemoglobin concentration predicted by the hypothesis. Both urban and rural older men have lower hemoglobin concentration than their young counterparts, a finding not attributable to age differences in nutritional status or testosterone concentration. Despite their relatively low hemoglobin concentration, older men have estimated arterial O2 content in the normal sea level range for young men and in this sense retain the capacity to adapt to high altitude at least through the seventh decade of life.

Fiberoptic bronchoscopy in the diagnosis of lung cancer comparison of pre-and post-bronchoscopy sputa, washings, bruchings and biopsies.

Fiberoptic bronchoscopy (brushings, washings and biopsies) was performed and pre- and post-bronchoscopy sputum cytologies obtained on 70 patients with histopathologically proven lung cancer. Bronchoscopy, with its associated procedures performed in 52 patients with primary bronchogenic carcinoma, was diagnostic in 41 (79%). Of all the various methods of obtaining specimens, bronchial brushing and bronchial biopsy gave the highest percentage yield (67%). However, since brush specimens could be obtained from peripheral lesions under fluoroscopic guidance, a greater number of positive specimens were obtained by this procedure (34) than by forceps biopsy (25), making brushing more useful. Pre- and post-bronchoscopy sputa were positive and thus of value in two cases when brushing and biopsy were both negative. Bronchial washing did not add significantly to the yield of positives and could therefore be eliminated as an unnecessary cost-and time-consuming procedure. Fiberoptic bronchoscopy was not helpful in diagnosing mediastinal tumors (5), lung metastases (7) and bronchial adenomas (6).

Thoracic aortic aneurysm causing acute bronchospasm.

Acute respiratory failure presenting as intractable bronchospasm was caused by tracheal obstruction due to an aneurysm of the thoracic aorta. Atropine was used successfully as a bronchodilating agent, as conventional therapy failed. The diagnosis was established by fiberoptic bronchoscopy.

Effects of expiratory loading on respiration in humans.

We examined the effects of expiratory resistive loads of 10 and 18 cmH2O.l-1.s in healthy subjects on ventilation and occlusion pressure responses to CO2, respiratory muscle electromyogram, pattern of breathing, and thoracoabdominal movements. In addition, we compared ventilation and occlusion pressure responses to CO2 breathing elicited by breathing through an inspiratory resistive load of 10 cmH2O.l-1.s to those produced by an expiratory load of similar magnitude. Both inspiratory and expiratory loads decreased ventilatory responses to CO2 and increased the tidal volume achieved at any given level of ventilation. Depression of ventilatory responses to Co2 was greater with the larger than with the smaller expiratory load, but the decrease was in proportion to the difference in the severity of the loads. Occlusion pressure responses were increased significantly by the inspiratory resistive load but not by the smaller expiratory load. However, occlusion pressure responses to CO2 were significantly larger with the greater expiratory load than control. Increase in occlusion pressure observed could not be explained by changes in functional residual capacity or chemical drive. The larger expiratory load also produced significant increases in electrical activity measured during both inspiration and expiration. These results suggest that sufficiently severe impediments to breathing, even when they are exclusively expiratory, can enhance inspiratory muscle activity in conscious humans.

Reproducibility of ventilatory measurements during sleep on different nights in patients with chronic obstructive pulmonary disease.

To evaluate the reproducibility of respiratory measurements between nights we performed studies in 20 outpatients with stable, moderately severe chronic obstructive pulmonary disease. All patients had symptoms from their lung disease but had no sleep complaints. Their mean age was 61 years, mean 1-second forced expiratory volume was 42% of predicted, and mean functional residual capacity 195% of predicted. Arterial Pco2 averaged 40 +/- 1 (SEM) mm Hg and mean Po2 64 +/- 1 mm Hg. Sleep was monitored for 7 hours by standard techniques on 2 nights 1 week apart. Breathing was assessed by measuring airflow at the nose and mouth with thermistors, and rib cage and abdominal respiratory movements with inductive plethysmography. Oxygen saturation was measured with an ear oximeter. Patients slept on the average 58% of the time in the first night and 63% in the second. Arousals were common but apneas uncommon in both nights. There was no significant difference in median nocturnal O2 saturation on the 2 nights. Tidal volume and minute ventilation, but not respiratory rate, were significantly lower and more variable in rapid eye movement (REM) sleep as compared with wakefulness and non-REM sleep; however, mean values and the variance for tidal volume, respiratory rate, or minute ventilation were similar on both nights.

Factors affecting respiratory system stability.

Periodic breathing (recurrent central apneas) occurs frequently during sleep. Periodic breathing can arise as a result of unstable behavior of the respiratory control system. A mathematical model of the respiratory control system was used to investigate, systematically, the effect of severity of disturbances to respiration and certain system parameters on periodic breathing occurring during sleep. The model consisted of multi-compartment representation of O2 and CO2 stores, a peripheral controller sensitive to O2 and CO2, and a central controller sensitive to CO2. The effects of hypoxia and hypercapnia on the upper airway muscles were not considered in the model. Episodes of hyperventilation or asphyxia were used to disturb the control system and explore the boundaries of stable breathing. Circulation time and metabolic rate were also varied. Simulations with the model produced the following findings: The number of central apneas associated with periodic breathing were greater as circulation time increased; controller gain increases also made the number of apneas greater, although periodic breathing occurs with lower controller gains as circulation time increases. At each level of circulation time there was a range of controller gain changes which caused little change in the number of apneas. There were more apneas with hypoxia; also the number of apneas increased with sleep-associated reductions in metabolic rate. The more rapidly resting PCO2 rose at sleep onset, the greater the likelihood of recurrent apneas. Finally, the more intense the disturbance, the more apneas there were.

Trimethoprim-sulfamethoxazole prophylaxis against urinary tract infection in the chronic spinal cord injury patient.

Suppressive therapy with antibiotics has long been thought to decrease the number of complications from the neuropathic bladder in spinal cord injury patients, but it may also induce resistance to antibiotics which subsequently causes difficulties in treating symptomatic urinary tract infections. Forty-three chronic spinal cord injury patients were randomized to continue to receive daily trimethoprim-sulfamethoxazole (TMP-SMX) urinary tract prophylaxis versus discontinuing antibiotic prophylaxis. Patients were all at least 6 months after spinal cord injury. Patients were followed for a minimum of 3 months, with weekly catheter urine cultures. The difference in the colonization rate at onset and after 3 months (percent of cultures with asymptomatic bacteriuria) between the control and prophylaxis group was not statistically significant (P > 0.1). There was a significant decrease in the percentage of TMP-SMX resistant asymptomatic bacteriuria in the control group, 78.8%, compared to 94.1% in the suppressive group (P < 0.05). There was no significant difference in the number of symptomatic urinary tract infections following the withdrawal of suppressive therapy between the control group, 0.035/week, and the prophylaxis group, 0.043/week (P > 0.5). There was a larger percentage of TMP-SMX resistant symptomatic urinary tract infections in the treated group, 42.5% versus 37.5% in the control group, but the difference was not significant (P > 0.5). Irrespective of the method of bladder management, suppressive therapy with TMP-SMX did not reduce the incidence of symptomatic bacteriuria and did increase the percentage of cultures resistant to TMP-SMX in asymptomatic patients.

Effect of quiet sleep on resting and CO2-stimulated breathing in humans.

We examined the effects of different levels of inspired CO2 on ventilation and the pattern of breathing in healthy adults during the awake and the stage II quiet-sleep states. During both states, subjects were studied supine with their heads enclosed in a canopy. Tidal volume (VT) was determined from quantitative measurements of abdominal and rib cage excursions with magnetometers. Inspired CO2 was raised by blending CO2-enriched gas into the airflow, which continuously flushed the canopy. During sleep, while room air was breathed, VT decreased significantly from 410 to 360 ml, and respiratory rate also fell from 17 to 16 breaths/min. As a consequence, ventilation was significantly reduced from 6.5 to 5.8 l/min, and end-tidal CO2 partial pressure (PCO2) rose from 39.1 to 42.5 Torr. Ventilatory responses to CO2 were reduced, on the average, during sleep to 79% of waking levels. The change in average inspiratory flow produced by CO2 was also less during sleep. Waking and sleeping ventilatory responses to CO2 correlated inversely with the rise in end-tidal PCO2 when room air was breathed during sleep. At all levels of VT, the rib cage contribution to VT was greater during quiet sleep than during wakefulness. These findings suggest that quiet sleep, in addition to depressing ventilation and the response to CO2 alters the manner in which VT is attained by rib cage and abdominal displacements.

Effects of continuous positive airway pressure after oleic acid-induced lung injury in dogs.

The physiologic effects of continuous positive airway pressure (CPAP) of 5,10,15, and 20 cm H2O during spontaneous ventilation were studied in six anesthetized dogs with simulated respiratory distress syndrome (RDS) induced by iv infusion of oleic acid and in three normal controls. After oleic acid, mean PaO2 dropped to 63.6 +/- 3.1 mm Hg while breathing 100% oxygen and mean shunt fraction was 48.3 +/- 3.0%. PaO2 and shunt fraction improved significantly at the two highest levels of CPAP (e.g.,PaO2 271.3 +/- 41.3 mm Hg and shunt fraction 17.8 +/-2.2% at 20 cm H2O CPAP). Mean mixed venous PO2 rose from 37.4 +/- 1.5 mm Hg with no CPAP TO 60.8 +/- 3.1 mm Hg at 20 cm H2O CPAP. Tissue oxygenation appeared to improve during CPAP, since cardiac output, oxygen delivery, and serum lactate were not significantly affected and mixed venous PO2 rose significantly. However, significant hypoventilation occurred at all but the lowest level of CPAP, mean PaCO2 rising from 44.1 +/- 1.8 mm Hg with no CPAP to 77.6 +/-6.8 mm Hg at 20 cm H2O CPAP. The hypoventilation during CPAP is consistent with increased work of breathing due to a combination of decreased lung compliance and increased dead space ventilation due to rapid, shallow breathing.

Effect of progressive hypoxia on breathing during sleep.

We examined the effects of progressive hypoxia on breathing during wakefulness and quiet (NREM) sleep in 17 healthy young adults (11 males and 6 females). Ventilation was determined from quantitative measurements of abdominal and rib cage excursions using magnetometers or inductive plethysmography. Hypoxia was induced by blending N2 into the inspiratory line of a loose-fitting mask while O2 saturation was monitored with an ear oximeter. No attempt was made to maintain isocapnia. Ventilatory responses to hypoxia were depressed in 2 male subjects by sleep, but were unchanged or increased in the others. Thus on the average, sleep produced no change in ventilatory responses to hypoxia. There was no consistent difference in the frequencies or tidal volumes attained at a given level of ventilation during hypoxia awake and asleep. During sleep there was relatively more rib cage than abdominal movement. Relief of hypoxia was followed by periodic breathing during sleep in 12 subjects but in only 2 subjects when awake. In two thirds of the trials, hypoxia failed to produce arousal even though arterial O2 saturation was allowed to fall below 75%. The results suggest that (1) sleep potentiates apnea producing effects of O2 changes but has inconsistent effects on ventilatory responses to hypoxia, and (2) hypocapnic hypoxia is not an invariably potent stimulus for arousal.

Arterial oxygen saturation over time and sleep studies in quadriplegic patients.

This study evaluated arterial oxygen saturation (SaO2) over time in a randomly selected group of quadriplegic patients to assess whether clinical history prospectively correlated with profiles of oxygen saturation. In 16 stable male quadriplegic patients (C4-T5), we used pulse oximetry to measure SaO2 over a 24 hour period. Measured values of SaO2 were formatted into a cumulative frequency distribution of SaO2 over time. The cumulative SaO2 values from the quadriplegic patients were compared to SaO2 values in a control group of 12 age-matched healthy male subjects. Ten quadriplegic patients had SaO2 profiles comparable to the range observed in healthy subjects. Six quadriplegic patients had SaO2 profiles outside of the normative range. These 6 exhibited cyclic desaturations (> 4%) during periods of behaviorally-defined sleep, suggestive of sleep-disordered breathing. During wakefulness, however, their values of SaO2 were within the normative range. With respect to level of injury, age, time after injury, or medication use, there was no difference between the six 'hypoxic' quadriplegic patients and the 10 'normoxic' quadriplegic patients. Five of the 6 hypoxic patients had a positive medical history of snoring and increased daytime sleepiness, as compared to 6 of 10 normoxic patients who gave a similar history. We also performed polysomnographic studies in a subgroup of 7 quadriplegic patients. In this subgroup, sleep-disordered breathing was observed in 3 patients (AHI of 54/53/12 per hour, respectively). We conclude that in quadriplegic patients, in whom there is a low clinical suspicion for sleep-disordered breathing, there can occur significant decreases in SaO2 over time.

Sleep apnea considered as a control system instability.

In the present study a mathematical model of the chemical control of respiration is described which attempts to simulate periodic breathing during sleep. The model is an extension of an earlier model which has been shown to successfully reproduce the transient effects of CO2 inhalation on breathing, controlled changes in ventilation on arterial gas tension, and Cheyne-Stokes breathing. Included in the extended model are the effects of chemical stimuli during sleep on both chest wall and upper airway muscle activity. Data is presented indicating that simulations from the model reproduce reasonably well the essential features of the results obtained in eight subjects with periodic respiration during sleep when breathing room air, O2, or low concentrations of CO2. Simulations from the model and the experimental data suggest that periodic breathing during sleep results from unstable operation in the respiratory control system analogous to that seen during instabilities in physical control systems. The model indicates that obstructive as well as central apneas can be produced by control system instability. Furthermore, central apneas increase the likelihood of obstructive apneas while obstructive apneas tend to aggravate the control instability. The model results predict that the characteristics of the periodic breathing seen during sleep, such as apnea length, will depend on circulation time and the sensitivity of both upper airway and chest wall muscles to hypercapnia and hypoxia.

Occlusion pressure and breathing pattern in patients with interstitial lung disease.

The ventilatory and occlusion pressure (P100) responses to hypercapnia, maximal inspiratory airway and transdiaphragmatic pressures, and the separate volume contributions of the rib cage and abdomen to tidal breathing were evaluated in 16 patients with chronic stable interstitial lung disease. Compared with those in the normal subjects, ventilation and P100 at a PCO2 = 55 mmHg were significantly higher (p less than 0.05 and p less than 0.01, respectively) in the patients with interstitial lung disease. However, the ventilatory and occlusion pressure responses to hypercapnia (delta VE/delta PCO2 and delta P 100/delta PCO2, respectively) were not significantly different between the groups. Maximal inspiratory airway pressure was significantly reduced in the patient group (p less than 0.05); maximal transdiaphragmatic pressure was also reduced but not significantly. At any given level of ventilation, tidal volume was decreased and breathing frequency increased in the patients with interstitial lung disease (p less than 0.05). The greater respiratory frequency was caused by reductions in both expiratory and inspiratory time. Because of smaller tidal volumes, rib cage expansion was reduced in the group of patients when compared with that in normal subjects during both spontaneous breathing and when compared at the same level of hypercapnia; abdomen volume was reduced to a lesser extent. We conclude that in patients with interstitial lung disease, non-chemical, presumably neural, mechanisms, increase respiratory drive and alter the breathing pattern. We speculate that both vagal mechanisms and mechanoreceptors in the chest wall sensitive to rib cage expansion contribute to these responses.