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| CONTENTS |
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| TOP CONTENTS SLEEP-DISORDERED BREATHING CONTROL OF BREATHING RESPIRATORY MUSCLES PULMONARY FUNCTION TESTING AND... REFERENCES |
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Epidemiology (3)
Risk Factors (1)
Pathophysiology (28)
Cardiovascular Mechanisms (12)
Upper Airway Mechanisms (9)
Control of Breathing (4)
Endocrinological Abnormalities (3)
Clinical Aspects (4)
In Critically Ill Patients (1)
Neuropsychological Function (3)
Diagnostic Techniques (5)
Treatment (11)
Airway Pressure and Flow (3)
Mandibular Devices (6)
Surgery (1)
Review Article (1)
Control of Breathing (15)
Studies in Animals (4)
Pathophysiological Studies in Volunteers (3)
Control of Breathing in Clinical Disorders (5)
Dyspnea (3)
Respiratory Muscles (16)
Studies in Animals (9)
Mechanical Ventilation (6)
General (3)
Pathophysiological Studies in Patients and Volunteers (1)
Contractility and Fatigue (1)
Diagnostic Studies (1)
Structure and Histology (2)
Respiratory Muscle Involvement in Clinical Disorders (3)
Pulmonary Function Testing and Bronchoscopy (11)
Equipment and Techniques (3)
Epidemiology Studies (3)
In Diabetes Mellitus (1)
Ciliary Function (1)
Bronchoscopy (3)
| SLEEP-DISORDERED BREATHING |
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| TOP CONTENTS SLEEP-DISORDERED BREATHING CONTROL OF BREATHING RESPIRATORY MUSCLES PULMONARY FUNCTION TESTING AND... REFERENCES |
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To determine the familial nature of obstructive sleep apnea and its cosegregation with sudden infant death syndrome, Gislason and coworkers (2) analyzed the Icelandic nationwide genealogy database of 2,350 patients with a diagnosis of sleep apnea and 58 infants with sudden infant death syndrome. The risk ratio for a first-degree relative of a patient with obstructive sleep apnea was 2.0. The kinship coefficient in the obstructive sleep apnea group was greater than in a control group. A nonsignificant trend was observed for relatedness between infants who died with sudden infant death syndrome and patients with severe obstructive sleep apnea syndrome. The authors conclude that a strong, familial relationship exists among Icelanders with obstructive sleep apnea syndrome.
In a state of the art review article, Young and colleagues (3) discuss the epidemiology of obstructive sleep apnea.
Risk Factors
To evaluate the feasibility and utility of acoustic pharyngometry for measuring upper airway dimensions, Monahan and coworkers (4) studied 203 children, aged 8 to 11 years, from a community-based cohort. The coefficient of variation for measurements of the minimum cross-sectional area of the pharynx was 11%. The minimum cross-sectional area was 1.17 cm2 in children who rarely or never snored; the area was decreased by 10% in children with habitual snoring and 18% in children with an apnea–hypopnea index of at least five events per hour. The mean cross-sectional area did not differ among the groups. The authors conclude that the minimum cross-sectional area of the pharynx is reduced in children with sleep-disordered breathing, and that acoustic pharyngometry is a useful technique for identifying risk factors for sleep-disordered breathing in preadolescent children.
Pathophysiology
Cardiovascular mechanisms.
To investigate the relevance of monocyte adhesive properties and oxidative metabolism to the pathogenesis of cardiovascular morbidity in the sleep apnea syndrome, Dyugovskaya and coworkers (5) studied 26 patients with obstructive sleep apnea and 31 healthy subjects. Sleep apnea syndrome was associated with increased expression of two adhesion molecules, CD15 and CD11c, in monocytes. Monocytes of the patients adhered more avidly to endothelial cells in culture than did monocytes from healthy subjects. Exposure of monocytes from healthy subjects to hypoxia in vitro caused upregulation of the expression of CD15 to levels comparable with the levels in the patients. Patients displayed increased production of reactive oxygen species in some subpopulations of monocytes and granulocytes. Treatment of eight patients with CPAP produced downregulation of CD15 and CD11c monocyte expression, decreased the basal production of reactive oxygen species by CD11+ monocytes, and decreased the adherence of monocytes to endothelium. The authors conclude that repeated hypoxic events cause endothelial and monocyte activation. An editorial commentary by Prabhakar (6) accompanies this article.
Because hypoxia is a major stimulus of vascular endothelial growth factor (a potent angiogenic cytokine), Lavie and coworkers (7) measured the plasma concentration of the cytokine in three sets of experiments. In 85 men (47 of whom had an apnea–hypopnea index greater than 20), the morning concentration of vascular endothelial growth factor was increased in proportion to the apnea–hypopnea index. During sleep, hourly levels of vascular endothelial growth factor were higher in five patients with sleep apnea (129 pg per ml) than in six snorers (75 pg per ml) or six healthy subjects (33 pg per ml). After treatment with CPAP for 1 year, nine patients experienced a decrease in vascular endothelial growth factor from 57 to 40 pg per ml; seven patients refusing CPAP therapy showed no change. The authors conclude that recurrent hypoxia in patients with sleep apnea is accompanied by increases in vascular endothelial growth factor.
Vascular endothelial growth factor is a hypoxia-sensitive glycoprotein that stimulates normal and abnormal new vessel growth. To determine whether repetitive nocturnal hypoxia can activate this growth factor, Schulz and coworkers (8) obtained peripheral venous blood samples at 7:00 A.M. from 10 patients with severe obstructive sleep apnea (lowest oxygen saturation, 57%), 10 patients with moderate sleep apnea (lowest oxygen saturation, 71%), and 10 healthy volunteers (lowest oxygen saturation, 86%). Vascular endothelial growth factor was 410 pg per ml in the severe group as compared with 224 pg per ml in the moderate group and 245 pg per ml in the healthy group. In the two patient groups, the growth factor was correlated with time that oxygen saturation remained below 90% (r = 0.67). The authors conclude that vascular endothelial growth factor is elevated in severely hypoxic patients with obstructive sleep apnea and that the level is related to the degree of nocturnal oxygen desaturation.
To investigate the nature of the vascular abnormality in patients with obstructive sleep apnea, Imadojemu and coworkers (9) studied eight patients with obstructive sleep apnea (apnea–hypopnea index, 47 events per hour) and nine healthy subjects. After a 10-minute occlusion of the arterial supply to the forearm, peak blood flow during reactive hyperemia and vascular conductance were lower in the patients than in the control subjects. Resting activity of muscle sympathetic nerves was higher in the patients than in the control subjects: 51 versus 30 bursts per minute. Two weeks of CPAP produced a 21% increase in reactive hyperemic blood flow, a 24% increase in forearm vascular conductance, and a decrease in activity of the muscle sympathetic nerves. The authors conclude that patients with sleep apnea have increased activity of the sympathetic nerves and an impaired maximal vasodilator response to an ischemic stimulus, and that both are improved by CPAP therapy.
Obstructive apneas during sleep are associated with transient increases in blood pressure. Imadojemu and coworkers (10) studied the mechanism of the pressor response in 11 patients with obstructive sleep apnea. Arterial pressure was higher immediately after an apnea as compared with the early stages of apnea. The increase in pressure was preceded by an increase in muscle sympathetic nerve activity, with no change in limb blood flow; vascular resistance in limb blood vessels increased by 29% after an apnea. Similar responses were seen with voluntary breathholds during wakefulness. Supplemental oxygen decreased the sympathetic nerve and vasoconstrictor responses to the apneas during both sleep and wakefulness. The authors conclude that increases in blood pressure in patients with sleep apnea are accompanied by transient vasoconstriction, which is mediated by the sympathetic nervous system and is also linked to hypoxia.
The reversibility of daytime pulmonary hypertension in patients with sleep apnea is uncertain. Sajkov and coworkers (11) used Doppler echocardiography to investigate this issue in 20 patients (average of 49 apnea–hypopnea events per hour) before and after 4 months of treatment with CPAP. Treatment decreased pulmonary artery pressure from 17 to 14 mm Hg and total pulmonary vascular resistance from 231 to 186 dyn · second · cm-5. Pulmonary vascular response to hypoxia (assessed at inspired oxygen concentrations of 11, 21, and 50%) decreased by 37%; a plot of pulmonary artery pressure versus cardiac output (measured during infusions of dobutamine) moved downward; and arterial diastolic pressure also fell. Improvements were not related to changes in left-ventricular diastolic pressure or oxygen tension. The authors conclude that CPAP reduces pulmonary artery pressure and the pulmonary vascular response to hypoxia in patients with obstructive sleep apnea.
Harrington and coworkers (12) studied cardiovascular autonomic function in 10 infants who had experienced an apparent life-threatening event and in 12 control infants. The studies were done during slow-wave sleep and rapid eye movement (REM) sleep. Five of the 10 infants who had experienced a life-threatening event had obstructive sleep apnea. Breathing during sleep was normal in the other five infants and in all of the control infants. In response to 45-degree head-up tilts, the infants with obstructive sleep apnea had a decreased heart rate response and three developed marked hypotension. The infants with sleep apnea also had altered variability of heart rate and blood pressure, and an increased threshold for arousal during REM sleep. The authors conclude that half of infants with an apparent life-threatening event have obstructive sleep apnea, and that this subgroup also has abnormal autonomic cardiovascular control.
To evaluate cardiac structure in children and adolescents with obstructive sleep apnea, Amin and coworkers (13) did echocardiography on 28 children with obstructive sleep apnea and 19 children with primary snoring. Left-ventricular mass index was 22% greater and relative wall thickness was 24% greater in the children with obstructive sleep apnea than in the children with primary snoring. An apnea–hypopnea index of 10 or more events per hour was associated with a 6.7-fold increased risk of enlarged right-ventricular dimensions and 11.2-fold increased risk of an increased left-ventricular mass index. The authors conclude that obstructive sleep apnea leads to cardiac remodeling and hypertrophy of both the right and left ventricles in children and adolescents.
To determine the risk of cardiovascular disease in patients with sleep apnea, Peker and coworkers (14) did a 7-year follow-up study of 182 middle-aged men. At baseline, subjects were free of hypertension, other cardiovascular diseases, diabetes mellitus, pulmonary disease, and other disorders; it was found that 60 subjects had obstructive sleep apnea and 122 did not. At least one cardiovascular disease developed in 37% of the cases with sleep apnea as compared with 7% of the cases without sleep apnea. On multiple logistic regression, development of cardiovascular disease was associated with sleep apnea at baseline (odds ratio, 4.9) and age (odds ratio, 23.4). Among the men with sleep apnea, cardiovascular disease occurred in 57% of the incompletely treated cases as compared with 7% of the effectively treated cases. Effective treatment was associated with decreased risk for cardiovascular disease (odds ratio, 0.1). The authors conclude that the risk of developing cardiovascular disease is increased almost fivefold in middle-aged men with obstructive sleep apnea, and that effective treatment decreases the risk to one tenth of that in untreated men.
The arterial baroreflex normally buffers acute changes in blood pressure through feedback modulation of sympathetic activity, and decreased efficiency of the reflex potentiates sympathetic hyperreactivity. To quantify the reflex, Bonsignore and coworkers (15) recorded blood pressure continuously (Finapres) during sleep. Variabilities of systolic pressure, diastolic pressure, and pulse interval were much greater in 29 normotensive patients with obstructive sleep apnea than in 11 healthy subjects. The patients had a lower sensitivity of the baroreflex during wakefulness and Stage 2 sleep than did the control subjects; sensitivity of the reflex was inversely related to the lowest oxygen saturation and to the increase in blood pressure after an apnea. Treatment with CPAP resulted in a lowering of heart rate, a decrease in the variability of blood pressure, and a 68% increase in the sensitivity of the baroreflex during Stage 2 sleep. The authors conclude that patients with obstructive sleep apnea have depressed baroreflex control of heart rate, which improves after treatment with CPAP.
To determine the effects of airflow limitation, with and without arousals, on peripheral vascular tone, O'Donnell and coworkers (16) studied 10 patients with obstructive sleep apnea. Patients were initially maintained on a therapeutic level of CPAP, and airflow limitation was induced through decreases in nasal pressure by as much as 7.4 cm H2O. Decreases in inspiratory airflow to less than 200 ml per second caused a 13% decrease in peripheral arterial tone; lesser decreases in airflow had no effect. The combination of decreases in inspiratory airflow plus arousals produced a greater decrease in peripheral arterial tone (23%). The authors conclude that severe airflow obstruction in patients with obstructive sleep apnea causes acute digital vasoconstriction and that the effect is accentuated by the presence of arousals.
Upper airway mechanisms.
To determine the pattern of growth for tissues surrounding the upper airway, Arens and coworkers (17) did magnetic resonance imaging in 92 healthy children between 1 and 11 years of age. In the midsagittal plane, the distance between the mental spine (point that the genioglossus is inserted into the mandible) and the clivus (passing through the centroid of the soft palate) was related linearly to age (r = 0.86). The dimensions of the tongue, soft palate, nasopharyngeal airway, and adenoids increased with age and maintained a constant proportion to the distance between the mental spine and the clivus. In the axial plane, the transverse distance between the mandibles was related to age (r = 0.78). The width of the tonsils, intertonsillar region, parapharyngeal fat pads, and pterygoids maintained a constant proportion to the intermandibular width with age. The authors conclude that the skeleton of the lower face grows linearly along the sagittal and axial planes between the first and eleventh years of life.
To determine the effects of craniofacial characteristics and body habitus on the collapsibility of the pharynx, Watanabe and coworkers (18) measured closing pressures of the passive pharynx in 54 men with sleep-disordered breathing. Static pressure–volume relationships for the velopharynx and oropharynx were measured endoscopically under general anesthesia and complete paralysis. Compared with 24 healthy subjects, the patients had receded mandibles, long lower faces, and downward development of the mandible on lateral cephalometry. Closing pressure was positive at the velopharynx alone in 50% of the patients, and at both the velopharynx and oropharynx in 44% of the patients. The patients who had positive closing pressures at both the velopharynx and the oropharynx had smaller maxillas and mandibles and less obesity than did the patients with positive closing pressure at the velopharynx alone. The authors conclude that obesity and craniofacial abnormalities contribute synergistically to an increase in tissue pressure surrounding the pharynx, leading to increases in collapsibility of the passive pharynx in patients with sleep-disordered breathing.
Activity of the dilator muscles of the pharynx is important in the pathogenesis of sleep apnea. To better understand the factors that influence activity of the genioglossus muscles, Malhotra and coworkers (19) studied 18 healthy volunteers during wakefulness. To discriminate between the relative influences of airway pressure and airflow, the subjects inhaled gases of differing densities (helium–oxygen, air). The genioglossal EMG signal was correlated with pressure in the epiglottis (range of r values, 0.71 to 0.83), and the relationship did not change despite variation in gas density or CO2 tension. The correlations between genioglossal activity and both flow and resistance were weaker. The authors conclude that negative pressure in the pharynx modulates activity of the genioglossus independently of respiratory drive.
Neither sustained hypercapnia alone nor brief resistive loading alone cause activation of the genioglossus during non-REM (NREM) sleep. To determine whether the combination of load and hypercapnia would cause activation, Stanchina and coworkers (20) recorded genioglossal electromyograms under varying combinations of inspiratory resistive loading (-5 to –15 cm H2O per liter per second), increases in PCO2 of 5 to 10 mm Hg, and oxygen saturations of 80 to 85% in 15 healthy subjects during NREM sleep. An increase in genioglossal activity occurred only with the combination of hypercapnia and resistive loading (activity increased to 247% of the baseline value). The authors conclude that genioglossal activity during NREM sleep is increased by the combination of resistive loading and hypercapnia, but not by either perturbation on its own.
The reason that men are at greater risk for obstructive sleep apnea than women is not clear. To address this issue, Malhotra and coworkers (21) studied the anatomic and physiologic features of the upper airway in 19 normal men and 20 normal women. Physiology of the upper airway was similar in the two groups during wakefulness; in particular, activation and responsiveness of the pharyngeal dilator muscles did not differ between the groups and pharyngeal mechanics were equivalent. The men displayed a 19% increase in airway length, a 33% increase in cross-sectional area of the soft palate, and an 80% increase in airway volume than did the women. A finite model of the upper airway based on signal-averaged data revealed substantially greater airway collapsibility in the men than in the women, based solely on anatomic differences. The authors conclude that greater risk for sleep apnea in men than in women is explained by the greater tendency for the pharynx to collapse as a result of anatomic factors, such as an increase in the length of the vulnerable airway and an increase in the size of the soft palate.
To investigate changes in lung and upper airway mechanics during various stages of sleep and arousals, Bijaoui and coworkers (22) studied seven men with obstructive sleep apnea (respiratory disturbance index, 56 events per hour). The onset of obstructed breathing was accompanied by a substantial increase in lung elastance, probably because of closure of some respiratory units. Pulmonary resistance was normal during wakefulness, but increased markedly in the presence of inspiratory flow limitation during sleep. The increase in resistance resulted almost completely from upper airway collapse. (Two new techniques were used to measure pulmonary resistance in the presence of flow limitation.) The authors conclude that patients with sleep apnea develop increased resistance in the upper airway and increased elastance of the lungs during obstructed breathing.
To determine whether snoring and obstructive sleep apnea is associated with structural changes in the epithelium of the upper airway, Paulsen and coworkers (23) obtained uvulae from 3 patients with habitual snoring, 9 patients with obstructive sleep apnea, and 43 control subjects. Scanning electron microscopy revealed a decrease or even an absence of connective tissue papillae in the patients as compared with the control subjects. Immunohistochemical staining revealed only weak or no staining for cytokeratin 13 in the epithelium of the patients. The distribution pattern for laminin did not differ among the groups. The patients had 1.4 times more leukocytes in the lamina propria of the uvular mucosa than did the control subjects, and most of these were CD3+ T lymphocytes. The authors conclude that patients with obstructive sleep apnea or snoring have structural abnormalities in the boundary between the subepithelium and connective tissue in the uvular mucosa.
To determine how activation of the pharyngeal muscles alters the relationship between cross-sectional area and airway pressure, Kuna and Brennick (24) did fiberoptic imaging in 10 decerebrate cats. They varied intraluminal pressure between –6 and 6 cm H2O and stimulated the distal ends of three nerves. Stimulation of the glossopharyngeal nerve produced a relatively constant increase in cross-sectional area across the range of pressures in the rostral oropharynx, velopharynx, and caudal oropharynx. Stimulation of the medial hypoglossus nerve produced significant interactions between pressure and stimulation in the rostral oropharynx. Combined stimulation of the hypoglossus branch and pharyngeal branch of the vagus nerve produced significant interactions between pressure and stimulation in the caudal oropharynx. Stimulation of the hypoglossal nerves caused greater increases in area of those regions in the lower pressure range. Stimulation of the pharyngeal branch of the vagus caused greater increases in area in the caudal oropharynx and velopharynx at the higher pressure range. The authors conclude that the mechanical effects of pharyngeal muscle activation depend not only on the region and on the particular muscle but also on the intraluminal pressure.
To determine whether endurance exercise training alters the oxidative capacity and phenotype of upper airway muscles, Vincent and coworkers (25) studied rats before and after performing treadmill exercise (90 minutes a day, 4 days a week) for 12 weeks. Training caused an increase in the activity of citrate synthase and superoxide dismutase in the digastric muscle, the sternohyoid muscle, and the costal diaphragm. There was a shift in the phenotype of the myosin heavy chain in the digastric, sternohyoid, and diaphragm: the content of the fast Type IIb isoform decreased, and the content of the slow Type I isoform increased. Training did not alter muscle phenotype, oxidative capacity, or antioxidant enzyme activity in the omohyoid or genioglossus muscles. The authors conclude that exercise training on a treadmill improves the oxidative and antioxidant capacity of the digastric and sternohyoid muscles, and that it promotes a shift in the phenotype of the myosin heavy chain from fast to slow isoforms.
Control of breathing.
Almost half of patients with congestive heart failure have periodic breathing and central sleep apnea. To better understand the pathogenesis, Xie and coworkers (26) studied 19 patients with congestive heart failure during NREM sleep; 12 of the patients had central sleep apnea and 7 did not. Compared with wakefulness, the patients without central apneas developed an increase in end-tidal PCO2 of 2.5 mm Hg during sleep; the patients with central apneas displayed no change in PCO2. Pressure support was used to lower PCO2 to determine the threshold for apnea. During eupnea, PCO2 was 5.1 mm Hg above the apnea threshold in the patients without central apneas, but only 2.8 mm Hg above the threshold in the patients with apneas. Below eupnea, the patients with apneas had a higher ventilatory response to CO2 than did the patients without apneas: 3.9 versus 1.5 liters per minute per mm Hg. The authors conclude that some patients with congestive heart failure develop central sleep apnea because their resting PCO2 is close to the apnea threshold as a result of heightened ventilatory sensitivity and a failure to develop the usual increase in PCO2 during sleep. An editorial commentary by Bradley (27) accompanies this article.
To study the effect of respiratory stimuli on respiratory motor output when PCO2 is lowered below the resting (eupneic) level, Nakayama and coworkers (28) studied chronically instrumented dogs during NREM sleep. Pressure support was used to lower PCO2; apneas occurred when PCO2 was 5 mm Hg below the resting level. This difference between resting PCO2 and the apnea threshold was taken as an index of susceptibility to apnea. An increase in the index, reflecting decreased susceptibility to apneas, occurred with respiratory stimulants: metabolic acidosis (6.7 mm Hg) and almitrine (5.9 mm Hg). A decrease in the index, reflecting increased susceptibility to apneas, occurred with a respiratory depressant, metabolic alkalosis (3.7 mm Hg). Hypoxia was an exception: despite producing an increase in ventilatory sensitivity to CO2 below eupnea, it caused a decrease in the index (4.1 mm Hg). The authors conclude that, contrary to conventional thinking, increases in respiratory drive can protect against the development of central sleep apnea. An editorial commentary by Bradley (27) accompanies this article.
To determine whether daytime PCO2 is related to the duration of ventilation between apneas, Ayappa and coworkers (29) studied 18 patients with sleep apnea (8 patients had a daytime PCO2 of higher than 45 mm Hg). The level of daytime PCO2 was not related to the average duration of apneas or to the average duration of ventilation between the apneas. Daytime PCO2, however, was correlated with the ratio of apnea duration to the duration of ventilation between the apneas (r = 0.48). The authors conclude that the relative balance between the duration of apneas and the duration of intervening ventilation is an important determinant of daytime hypercapnia in patients with obstructive sleep apnea syndrome.
Endocrinological abnormalities.
To determine the relationship between sleep-disordered breathing and insulin resistance, Ip and coworkers (30) studied 250 consecutive subjects without known diabetes mellitus; 185 had an apnea–hypopnea index of at least 5 events per hour. Patients with sleep apnea were more insulin resistant, as indicated by a 30% higher level of fasting serum insulin and a 39% higher value on the homeostasis model assessment method (fasting serum insulin x fasting plasma glucose); the patients were also older and more obese. Stepwise multiple linear regression showed that obesity was the major determinant of insulin resistance, but apnea–hypopnea index and minimum oxygen saturation were also independent determinants. The association between sleep apnea and insulin resistance was seen in both obese and nonobese subjects. The fasting level of insulin increased by about 0.5% for each additional apnea or hypopnea per hour of sleep. The authors conclude that sleep-disordered breathing is an independent risk factor for insulin resistance. An editorial commentary by Tasali and Van Cauter (31) accompanies this article.
To determine the relationship between glucose intolerance and insulin resistance with sleep-disordered breathing, Punjabi and coworkers (32) recruited 150 mildly obese, but otherwise healthy, men from the community. The prevalence of sleep-disordered breathing ranged from 40 to 60%, depending on the threshold apnea–hypopnea index. After adjusting for body mass index and percent body fat, an apnea–hypopnea index of at least 5 events per hour was associated with an increased risk of impaired glucose tolerance (odds ratio, 2.15). The odds ratio for worsening glucose tolerance was 1.99 for a 4% decrease in oxygen saturation. Multivariable linear regression analyses revealed that an increasing apnea–hypopnea index was associated with worsening insulin resistance, independently of obesity. The authors conclude that sleep-disordered breathing is independently associated with glucose intolerance and insulin resistance. An editorial commentary by Tasali and Van Cauter (31) accompanies this article.
Clinical Aspects
In critically ill patients.
To determine whether the quality of sleep is altered by the mode of mechanical ventilation, Parthasarathy and Tobin (33) studied 11 critically ill patients. All patients achieved sleep. Sleep fragmentation, measured as the sun of arousals plus awakenings, was greater during pressure support than during assist-control ventilation: 79 versus 54 events per hour. Six of the 11 patients developed central apneas during pressure support but not during assist-control ventilation by virtue of the backup rate. Heart failure was more common in the 6 patients who developed apneas than in the 5 patients without apneas: 83 versus 20%. Among the patients with central apneas, adding dead space (which increased end-tidal PCO2 by 4.3 mm Hg) decreased the sum of arousals plus awakenings from 83 to 44 events per hour. The number of central apneas was most closely related to the difference between end-tidal CO2 (during a mixture of wakefulness and sleep) and the apnea threshold point (r = -0.83). In patients receiving pressure support, respiratory rate was 32.6% lower and end-tidal CO2 was 11.0% higher during sleep than during wakefulness. In patients receiving assist-control ventilation, respiratory rate was 14.9% lower and end-tidal CO2 was 4.6% higher during sleep than during wakefulness. The authors conclude that critically ill patients experience greater fragmentation of sleep during pressure support than during assist-control ventilation because of the development of central apneas, and that this effect is especially prominent in patients with heart failure.
Neuropsychological function.
The threshold for arousal in response to an inspiratory load is increased in patients with sleep apnea. To determine whether patients with sleep apnea display a decrease in the cortical response to a mid-inspiratory occlusion and whether the response differs between wakefulness and sleep, Gora and coworkers (34) studied 6 patients with mild obstructive sleep apnea (respiratory disturbance index, 5 to 15 events per hour) and 6 control subjects. During wakefulness, electroencephalography revealed broadly similar evoked potentials in response to a mid-inspiratory occlusion in both the patients and the control subjects. During Stage 2 sleep, the N550 component in the average K-complex response to occlusion was much reduced in the patients. The decreased response to the occlusion was secondary to both a smaller proportion of elicited K complexes and to smaller amplitude of the K complexes. The authors conclude that patients with mild obstructive sleep apnea display a blunted cortical response to a mid-inspiratory occlusion during Stage 2 sleep, but that the abnormality is not related to impaired mechanoreceptor function because the evoked response is normal during wakefulness.
Repeated episodes of hypoxia, hypercapnia, and hypertension associated with sleep apnea may produce brain damage; also, brain damage may predispose to sleep apnea. To determine whether patients display anatomic abnormalities in the brain, Macey and coworkers (35) did high-resolution magnetic resonance imaging in 21 patients with obstructive sleep apnea (apnea–hypopnea index ranging from 8 to 95 events per hour) and 21 control subjects. The patients displayed loss of gray matter in multiple sites (up to 18% in some regions), including the frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum. The loss of gray matter occurred within sites that are involved in motor regulation of the upper airway and in areas contributing to cognitive function. Unilateral loss in well-perfused structures suggests that neural deficits may begin early in patients with sleep apnea. Total volume of gray matter decreased with age in the control subjects, but not in the patients. The authors conclude that the volume of gray matter in the brain is reduced in patients with obstructive sleep apnea in proportion to the severity of the apneas, and that the abnormalities may be a consequence of apneas, may contribute to the genesis of apneas, or both. An editorial commentary by Gozal (36) accompanies this article.
Diagnostic Techniques
The reference standard for identifying apneas and hypopneas is the recording of flow with a pneumotachograph but this can disrupt sleep. To assess the reliability of less obtrusive methods, Heitman and coworkers (37) studied 11 patients with a mean respiratory disturbance index of 49. Two individuals scored a random sample of 550 events as apnea/hypopnea or no event. The kappa values for inter-measurement agreement with the pneumotachograph were 0.76 for nasal pressure, 0.73 for a square-root transformation of nasal pressure, and 0.50 for respiratory inductive plethysmography. Inter-rater agreements were 0.68 for the pneumotachograph, 0.66 for nasal pressure, 0.61 for square-root transformation of nasal pressure, and 0.47 for respiratory inductive plethysmography. Intra-rater agreements were 0.60 for the pneumotachograph, 0.82 for nasal pressure, 0.78 for square-root transformation of nasal pressure, and 0.76 for respiratory inductive plethysmography. The authors conclude that monitoring of nasal pressure is a reproducible method that closely agrees with pneumotachography in detecting apneas and hypopneas, and its accuracy is not enhanced by a square-root transformation of the pressure signal. An editorial commentary by Montserrat and Farre (38) accompanies this article.
Measurement of airflow at the nose with a thermistor or measurement of pressure at the nose with a cannula is used in the detection of apneas and hypopneas. Trang and coworkers (39) compared the accuracy of the two techniques in 14 infants (aged, 2.6 months) and 16 children (aged 5.5 years) with suspected obstructed sleep apnea. All children tolerated the nasal cannula. A noninterpretable flow signal lasting more than 20% of total sleep time occurred in five children using a cannula versus only one child using the thermistor. A total of 465 obstructive apneas were identified: 43% of the apneas were detected by both techniques; 52% of the apneas missed by the thermistor were detected by nasal pressure monitoring; and only 5% of the apneas missed by nasal pressure were detected by the thermistor. A total of 159 obstructive hypopneas were detected: nasal pressure detected 100% of these events whereas the thermistor detected only 14%. Esophageal pressure was recorded in six children; all events detected by nasal pressure were associated with increased airway resistance. The authors conclude that measurement of pressure at the nose with a nasal cannula is more reliable than measurement of flow with thermistors in detecting obstructive apneas and hypopneas in children.
Steltner and coworkers (40) developed a new algorithm for automated detection and classification of apneas and hypopneas. The algorithm is based on time-series analysis of nasal mask pressure and a forced oscillation signal related to respiratory input impedance. The polysomnogram signals of 19 subjects with suspected sleep-disordered breathing were scored by two experts. There was no discrepancy between automated scoring and scoring by the experts. The authors conclude that a new algorithm for automatic detection and classification of sleep-disordered breathing provides results comparable to scoring performed by experts.
The OSLER test is an alternative to the maintenance of wakefulness test. Mazza and coworkers (41) studied the usefulness of the OSLER test in characterizing daytime sleepiness in 27 patients with obstructive sleep apnea (apnea–hypopnea index, 43 events per hour) and 20 healthy subjects. The tests were performed at 9:00 A.M., 11:00 A.M., and 1:30 P.M. Mean sleep latency time was 1,788 seconds in the patients as compared with 2,335 seconds in the control subjects. The patients spent a greater percentage of time making errors than did the control subjects: 5.4 versus 0.4%. Of patients who had normal sleep latency, 40% were classified as exhibiting abnormal fluctuations in vigilance on the basis of their error profile. A single OSLER test at 9:00 A.M. was as sensitive in detecting abnormal daytime sleepiness as the combination of three consecutive tests. The test at 1:30 P.M. was the least specific in distinguishing patients from the healthy subjects. The authors conclude that OSLER is a strong test for detecting daytime sleepiness in patients with sleep apnea.
Treatment
Airway pressure and flow.
To determine the effect of CPAP in patients with mild obstructive sleep apnea, Barnes and coworkers (42) did a randomized crossover trial of CPAP versus a placebo tablet. Of 42 patients with apnea–hypopnea index of 5 to 30 (average 13) events per hour, 28 completed both treatment arms. CPAP produced improvement in self-reported snoring, restless sleep, daytime sleepiness, and irritability. CPAP did not improve multiple sleep latency, sleepiness on the Epworth Scale, neurobehavioral function on quality of life questionnaires, or 24-hour blood pressure. Placebo achieved improvement in many functional variables. The authors conclude that nasal CPAP failed to improve measures of objective or subjective daytime sleepiness in patients with mild sleep-disordered breathing, and that the placebo effect may account for some of the treatment responses previously reported. An editorial commentary by Engleman (43) accompanies this article.
A new generation of CPAP devices that provide automatic adjustment of applied pressure is commercially available. The algorithms employed by the devices are not well known and are likely to vary from device to device. Farre and coworkers (44) developed a bench-testing protocol to characterize the response of five commercial devices: DeVilbis AutoAdjust LT, Autoset Portable II Plus, Autoset-T, Virtuoso-LX, and Goodnight 418P. A waveform generator reproduced the pattern of breathing previously recorded in patients with sleep apnea (normal, apneas, hypopneas, flow limitation, and snoring). The response of the five devices varied considerably. When subjected to repetitive apneas, two of the devices did not modify the level of CPAP and the other three devices developed increases in pressure at different rates (ranging from an increase of up to 10 cm H2O over 3 minutes to an increase of up to 16 cm H2O over 8 minutes). Responses to air leaks varied among the devices. The authors conclude that devices for providing automatic adjustment of CPAP vary greatly in their response and the response of one device in a clinical trial cannot be generalized to other devices.
Mandibular devices.
To determine the effectiveness of a mandibular advancement splint in the treatment of patients with obstructive sleep apnea, Gotsopoulos and coworkers (45) did a randomized control trial in 73 patients (respiratory disturbance index of 27 events per hour). Compared with an inactive oral appliance, the active splint produced improvements in sleep latency on a multiple sleep latency test (10.3 versus 9.1 minutes) and in the Epworth sleepiness score (7 versus 9 minutes). The proportion of patients with normal subjective sleepiness was higher in the active splint group (82 versus 62%), although objective sleepiness did not differ between the two groups. The authors conclude the four weeks of treatment with a mandibular advancement splint improves daytime sleepiness and a range of other symptoms in patients with obstructive sleep apnea.
In 48 patients with sleep apnea (apnea–hypopnea index of 22 events per hour), Engleman and coworkers (46) did a randomized crossover trial of 8 weeks of CPAP versus 8 weeks of treatment with a mandibular repositioning splint. Seven of 21 measured variables improved to a significantly greater extent with CPAP than with the splint: apnea–hypopnea index (8 versus 15 events per hour), Epworth sleepiness scale (8 versus 12), effectiveness rating, functional outcomes of sleepiness on a questionnaire, the mental component on short-form SF health survey and health transition scores. No differences between the two treatments were seen for objective sleepiness, cognitive performance, and preference for treatment. Patients with mild disease (apnea–hypopnea index of less than 15 events per hour) also had a better response to CPAP than with the splint. The authors conclude that a mandibular repositioning splint does not represent the first-line treatment of patients with sleep apnea syndrome.
To determine the efficacy and tolerance of an oral jaw-positioning appliance in children with sleep apnea, Villa and coworkers (47) studied 32 patients (aged 4 to 10 years). Nineteen patients were randomized to 6 months treatment with the device and 13 served as controls. Four treated patients and five untreated patients were lost to follow up. Of the 14 treated patients, 9 (64%) showed a 50% or greater decrease in apnea–hypopnea index. Symptoms of sleep apnea decreased in all treated patients and completely resolved in half. Untreated patients showed no change. The authors conclude that use of a jaw-positioning appliance is effective in treating sleep apnea in children and the appliance is reasonably well tolerated.
The effectiveness of a mandibular advancement device is usually evaluated after several weeks of use. To determine whether the effectiveness could be judged during a single night of polysomnography, Petelle and coworkers (48) studied seven patients with obstructive sleep apnea. During an initial titration night, a hydraulic system connected to two lateral arches advanced the mandible by 1 mm every 15 minutes. The mean advance was 13 mm. The patients were then fitted with a permanent device, set at the final advancement achieved during the titration night, and another polysomnogram was performed. Apnea–hypopnea index was 67 events per hour at baseline, 26 events per hour during the titration night, and 20 events per hour during the treatment night. The authors conclude that it is possible to judge the efficacy of a mandibular advancement device during a single night of polysomnography.
To determine the proportion of patients with contraindications to the use of a mandibular advancement device, Petit and coworkers (49) studied 100 unselected patients with sleep apnea. The clinical charts and X-rays were analyzed by two expert maxillofacial surgeons (one blinded to the other). The surgeons agreed on absolute contraindications in 96 of the 100 patients. Contraindications were found in 34% of the patients. Contraindications included: insufficient remaining teeth (mean tooth loss was eight); periodontal abnormalities in half the patients; and a disorder of the temporomandibular joint in two patients. Sixteen patients required dental and periodontal care before use of the mandibular advancement device. The authors conclude that about a third of patients with sleep apnea syndrome have contraindications to the use of a mandibular advancement device.
To determine whether the efficacy and acceptance of a mandibular advancement splint is influenced by the extent that it increases bite opening along the vertical axis, Pitsis and coworkers (50) did a randomized crossover trial in 23 patients with obstructive sleep apnea. Patients were randomized to splints that produced inter-incisal opening of either 4 or 12 mm for over 2 weeks, followed by washout for 1 week, and the other splint was then applied for another 2 weeks. Compared with an apnea–hypopnea index of 21 events per hour at baseline, the 4-mm splint decreased the index to 8 events per hour and the 12-mm splint decreased the index to 10 events per hour. The apnea–hypopnea index decreased by at least 50% and to 6 or fewer events per hour in 74% of the patients treated with the 4-mm splint and in 61% of the patients treated with the 12-mm splint. Patient preference was greater for the 4-mm splint than for the 12-mm splint: 78 versus 22%. The authors conclude that a mandibular advancement splint that induces 4 mm of bite opening is as effective as a splint that induces 12 mm of bite opening, but patients prefer a splint that produces a smaller degree of bite opening.
Surgery.
In 20 nonobese habitual snorers who did not display significant oxygen desaturation or excessive daytime sleepiness, Back and coworkers (51) studied the effect of thermal ablation of the soft palate using bipolar radiofrequency. The major site of obstruction was located at the soft palate, and the patients received two treatments, one week apart, on an outpatient basis. Evaluation by questionnaire and visual analog scale revealed decreases in snoring and daytime sleepiness. Magnetic resonance imaging revealed changes in the dimensions of the soft palate and in the T1-signal intensity. The authors conclude that thermal ablation of the soft palate decreases snoring and daytime sleepiness in habitual snorers who do not have oxygen desaturation and excessive daytime sleepiness.
Review article.
In a clinical commentary, George and colleagues (52) discuss across-country viewpoints on sleepiness during driving.
| CONTROL OF BREATHING |
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| TOP CONTENTS SLEEP-DISORDERED BREATHING CONTROL OF BREATHING RESPIRATORY MUSCLES PULMONARY FUNCTION TESTING AND... REFERENCES |
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Exposure to maternal smoking during pregnancy is a risk factor for sudden infant death, but the relative contributions of nicotine and other substances in cigarette smoke to this effect are not clear. Hafstrom and coworkers (54) exposed fetal lamb to nicotine at a dosage comparable to mild-to-moderate cigarette smoking. At 5 and 21 days after delivery, the nicotine-exposed lambs had a lower tidal volume and higher respiratory rate than did nonexposed control lambs. Nicotine-exposed lambs had a higher airway occlusion pressure and higher effective impedance on the fifth day after delivery. The authors conclude that in utero exposure to nicotine results in postnatal abnormalities in the control of breathing, most likely because of increased impedance in the respiratory system.
Maternal smoking is a major risk factor for late fetal death and the sudden infant death syndrome. To determine the effect of prenatal exposure to nicotine on postnatal defense against hypoxia, Hafstrom and coworkers (55) exposed 7 lambs to nicotine during the last trimester of pregnancy. At five days after birth, lambs with prenatal exposure to nicotine had a lower ventilatory response to hypoxia during quiet sleep than had control lambs. The time to arouse from sleep after exposure to hypoxia was more than twice as long in the nicotine-exposed lambs. The heart rate response to hypoxia was lower during both sleep and wakefulness in the lambs than had been exposed to prenatal nicotine. During wakefulness, the ventilatory response to hypoxia was equivalent in the two groups. The ventilatory response to hyperoxia was lower in the nicotine-exposed lambs during both wakefulness and sleep. The transition from wakefulness to sleep was associated with a decrease in ventilation in the control lambs, but not in the nicotine-exposed lambs. The authors conclude that exposure to a low dose of nicotine during the last trimester of pregnancy blunts the ventilatory, heart rate, and arousal responses to hypoxia in newborn lambs. An editorial commentary by Nattie and Kinney (56) accompanies this article.
Pathophysiological Studies in Volunteers
To determine whether breath-to-breath variability of breathing is influenced by chemoreceptor reflexes, Van den Aardweg and Karemaker (57) studied 19 healthy subjects during resting breathing. While breathing air, 15 subjects displayed coherent oscillations in end-tidal CO2 and mean inspiratory flow; the frequencies were mostly below 0.15 cycles per breath. While breathing 100% oxygen, only 8 subjects had coherent oscillations in end-tidal CO2 and mean inspiratory flow. The oscillations in mean inspiratory flow were in phase with inspiratory volume. The gain and phase of the coherent oscillations in end-tidal CO2 and mean inspiratory flow could be explained by a theoretical model that included chemoreflex feedback, but could not be explained without inclusion of chemoreflexes. The authors conclude that variability of breathing is not a random process and that their methodology makes it possible to study chemoreceptor function without applying external stimuli. An editorial commentary by Bruce (58) accompanies this article.
To gain insight into the effect of vagally-mediated reflexes on the control of swallowing, Yamamoto and Nishino (59) induced reflex swallowing in 13 healthy subjects by infusing distilled water into the pharynx. Voluntary hyperpnea (which augments vagally-mediated reflexes) decreased the frequency of swallowing irrespective of whether end-tidal CO2 fell or remained constant. Breathholding (which attenuates vagally mediated reflexes) caused an immediate increase in the frequency of swallowing. During the hyperpnea that immediately followed the breathholds, the frequency of swallowing decreased immediately. The coupling of swallowing with expiratory time was lost during voluntary hyperpnea. The authors conclude that vagally-mediated reflexes influence the control of swallowing frequency and the timing of swallowing in reference to the respiratory cycle.
Control of Breathing in Clinical Disorders
To determine whether the variability of breathing pattern is altered in patients with restrictive lung disease and to determine whether any such alteration is related to dyspnea, Brack and coworkers (60) measured ventilation nonobtrusively in 10 patients with restrictive lung disease and in 7 healthy subjects. Compared with the healthy subjects, the random fraction of breath variability was reduced in the patients: 27 times for expiratory time, 12 times for tidal volume, and 6 times for inspiratory time. Conversely, the nonrandom, correlated fraction for tidal volume was increased almost threefold in the patients. On a separate occasion, dyspnea was measured while the patients and control subjects voluntarily copied different tidal volumes and frequencies. Small variations from the average resting tidal volume caused marked increases in dyspnea in the patients, and the relationship was parabolic (r2 = 0.97). The authors conclude that patients with restrictive lung disease adopt a tightly constrained breathing pattern, probably as a strategy for avoiding dyspnea.
To determine factors that lead to an increase in PCO2 during exercise, O'Donnell and coworkers (61) studied 20 patients with COPD (FEV1, 34% of predicted). During maximum cycle exercise, patients increased PCO2 by 7 mm Hg (range, -6 to 25 mm Hg). The change in PCO2 from rest to exercise was best correlated with the change in PCO2 while breathing 60% oxygen (an indirect test of ventilation-perfusion mismatching; r2 = 0.62) and with resting oxygen saturation (r2 = 0.30). Serial changes in PCO2 during exercise were most closely correlated with changes in end-expiratory lung volume (r = 0.56) and oxygen saturation (r = 0.82). The authors conclude that the development of hypercapnia during exercise in patients with COPD is related to the development of dynamic hyperinflation and abnormalities of ventilation-perfusion matching. An editorial commentary by Dempsey (62) accompanies this article.
The cause of congenital central hypoventilation syndrome is unknown, although a genetic etiology is suspected. Sritippayawan and coworkers (63) describe a 25-year-old woman with congenital central hypoventilation who gave birth to an infant with the same condition. The mother did not have worsening of symptoms during pregnancy and her ventilatory response to hypercapnia was unchanged. The mother was managed by diaphragmatic pacing throughout pregnancy. The authors conclude that the presence of congenital central hypoventilation syndrome in both a mother and daughter supports a dominant mode of inheritance for the condition.
Failure to recognize the severity of an attack of asthma is associated with asthma deaths. To determine whether patients with asthma have problems in processing perceptual information, Webster and Colrain (64) studied respiratory and auditory evoked responses in 16 patients with asthma and 16 healthy subjects. On breathing against four resistive loads, magnitude estimation on a modified Borg scale was linearly related to the intensity of the resistive load in both the patients (r2 = 0.96) and the control subjects (r2 = 0.99). Respiratory-related evoked potentials were measured with scalp encephalograms in response to inspiratory occlusions of 200-millisecond duration. P3 (the amplitude at 250 to 350 milliseconds after the change in mouth pressure) was smaller in the patients with asthma than in the control subjects: 16.9 versus 22.9 µV. The P3 component of the evoked potential in response to auditory signals was also lower in the patients than in the control subjects: 13.2 versus 18.6 µV. The authors conclude that patients with asthma have an impaired capacity for perceptual processing of respiratory and auditory information.
Dyspnea
The respiratory sensation of increased effort to breathe occurs with many respiratory disorders, but the sensation of chest tightness is unique to bronchoconstriction. To determine whether tightness is related to work of breathing, Binks and coworkers (65) used methacholine to induce a 16% decrease in the FEV1/FVC ratio in 15 subjects with mild asthma. Methacholine produced sensations of both increased effort and tightness in all subjects. Mechanical ventilation produced a 16% decrease in the sense of effort, but it did not significantly reduce the sense of tightness as compared with spontaneous breathing. An increase in end-expiratory volume of 279 ml occurred with methacholine; an equivalent increase in end-expiratory volume, induced by positive end-expiratory pressure, did not produce increased effort or tightness. The authors conclude that an increase in respiratory work contributes to the sense of effort but not to the sense of chest tightness that accompanies acute bronchoconstriction in patients with asthma. An editorial commentary by Davenport (66) accompanies this article.
To determine the role of rib-cage and intercostal muscle afferents in respiratory sensation during induced bronchoconstriction, Lougheed and coworkers (67) studied six patients with complete C4–C7 quadriplegia who did not require assisted ventilation. A high dose of methacholine caused FEV1 to decrease by 1.42 liter (62% predicted) and inspiratory capacity to decrease by 0.89 liter (30% predicted). Dyspnea was rated as moderate or severe. The predominant qualitative sensations were inspiratory difficulty and unsatisfied inspiration. Dyspnea was linearly correlated with the change in inspiratory capacity (r2 = 0.80); adding changes in FEV1, breathing pattern, and esophageal pressure did not strengthen the relationship. The changes in lung volume, intensity of dyspnea, and quality of dyspnea were similar to those seen in patients with asthma. The authors conclude that the intensity and quality of dyspnea during acute bronchoconstriction and hyperinflation is not altered by extensive chest-wall deafferentation.
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| TOP CONTENTS SLEEP-DISORDERED BREATHING CONTROL OF BREATHING RESPIRATORY MUSCLES PULMONARY FUNCTION TESTING AND... REFERENCES |
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The heavy chain isoform of the myosin molecule is the main determinant of muscle contractility. To determine whether controlled mechanical ventilation alters expression of the myosin heavy chain of individual myofibers, Yang and coworkers (70) studied rats that received controlled ventilation for up to four days in conjunction with anesthesia and neuromuscular blocking agents. The ratio of diaphragmatic weight to body weight decreased by 13.4% in the ventilated rats; the ratio did not decrease significantly in a control group or in rats that were anaesthetized but continued to breathe spontaneously. The ventilated rats experienced a decrease in pure type I myofibers in the diaphragm and about a fivefold increase in the percentage of hybrid fibers (fibers expressing both type l and type II myosin isoforms). The percentages of type I, type II, and hybrid fibers in limb muscles did not differ among the three experimental groups. Mechanical ventilation produced about a 50% decrease in both maximal twitch force and maximal tetanic force in muscle strips. The authors conclude that controlled mechanical ventilation for up to four days causes significant remodeling and functional alterations in the rat diaphragm. An editorial commentary by Sassoon (71) accompanies this article.
Prolonged mechanical ventilation can cause diaphragmatic atrophy. To determine the role of proteolytic activity and oxidative injury in causing diaphragmatic atrophy, Shaneley and coworkers (72) randomized rats to three groups: 18 hours of controlled ventilation, 18 hours of anesthesia while breathing spontaneously breathing, and a brief period of acute anesthesia. Mechanical ventilation produced a decrease of 10% in total diaphragmatic mass, a decrease of 11% in costal diaphragmatic mass, and decreases in the cross-sectional area of all four muscle fibers (Types I, IIa, IId/x, and IId). Mechanical ventilation fostered the degradation of diaphragmatic protein, associated with an increase of 128% in calpain-like activity and an increase of 470% in activity of the 20S proteasome. Mechanical ventilation caused protein oxidation (as reflected by an increase in protein carbonyl levels) and lipid oxidation (as reflected by an increase in 8-isoprostane concentration). The authors conclude that 18 hours of mechanical ventilation causes atrophy of all four types of diaphragmatic fibers in association with increases in protein degradation and oxidative stress. An editorial commentary by Hussain and Vassilakopoulos (73) accompanies this article.
General.
Duchenne muscular dystrophy and the mdx mouse are characterized by the lack of dystrophin, a protein that connects the cytoskeleton of the sarcolemma to the extracellular matrix. Coirault and coworkers (74) studied the interaction between actin and myosin in 9-month-old male mdx mice and control mice. In the diaphragm, the sliding velocity of actin filaments over monomeric myosin was 36% slower in the mdx mice than in control mice. In limb (semitendinosous) muscle, no difference was seen between the two groups. Compared with control mice, the diaphragm of the mdx mice exhibited a shift in the myosin isoform composition (MHC) from type IIX to type IIA accompanied by a reduction in type IIB. The limb muscles of the two groups of animals consisted almost exclusively of the type IIB isoform. The authors conclude that myosin extracted from the diaphragm of mdx mice moves actin filaments at a lower velocity than does myosin from the diaphragm of control mice despite the lack of significant change in the slow-to-fast ratio in myosin isoforms.
Reactive oxygen species are produced inside skeletal muscles under normal and pathological conditions. Javesghani and coworkers (75) determined whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase could be the source of reactive oxygen species in muscle fibers. (NADP catalyzes the production of superoxide by the transfer of one electron of oxygen, using NADPH or NADH as the electron donor.) The addition of NADH caused a 13-fold increase in the production of superoxide anion in muscle strips from normal rats. The production of superoxide anion and NADH consumption were inhibited by Tiron, superoxide dismutase, apocynin, and diphenyleneiodonium. Production was not abrogated by inhibitors of cyclooxygenases, xanthine oxidase, nitric oxide synthases, and mitochondrial enzymes. The enzyme complex was localized in close proximity to the sarcolemma and it consisted of at least four subunits: p 22phox, gp91phox, p47phox, and p67phox. The induction of sepsis in rats doubled the production of superoxide anion by muscle, without causing a major change in the expression of the NADPH oxide subunit in muscle. Inhibition of nitric oxide synthase caused a significant increase in the production of superoxide anion in endotoxin-treated muscles but not in control muscles. The authors conclude that a NADPH oxidase enzyme complex, which is constitutively active in the skeletal muscle fibers of normal rats, contributes to the production of reactive oxygen species, and that production of reactive oxygen species is increased in septic rats despite enhanced production of nitric oxide causing a decrease in superoxide anions.
Tumor necrosis factor- stimulates muscle wasting and induces muscle contractility without overt catabolism. Reid and coworkers (76) studied the relative sensitivity of the diaphragm and limb muscles of rats to tumor necrosis factor-. Across a range of stimulus frequencies, tumor necrosis factor- caused depression of tetanic force in the diaphragm and in flexor digitorum brevis. In isolated muscle fibers, the decrease in tetanic force was shown to be independent of the level of resting calcium and of alteration in calcium transients. The authors conclude that tumor necrosis factor- produces equivalent depression of the contractile response of the diaphragm and limb muscles, and that the depression is secondary to blunting of the response of myofilaments to calcium activation.
Pathophysiological Studies in Patients and Volunteers
Contractility and fatigue.
Breathing against an inspiratory resistive load is known to produce increases in plasma cytokines. Vassilakopoulos and coworkers (77) asked, "Are monocytes the source of the cytokines released during resistive breathing and are reactive oxygen species the stimuli for the release?" Six healthy men generated 75% of maximal inspiratory pressure for 45 minutes, and experienced twofold increases in plasma levels of tumor necrosis factor- and interleukin-6, and a threefold increase in interleukin-1ß. A second session of resistive breathing was performed after the administration of a combination of antioxidants (vitamin A, vitamin C, and vitamin E for 60 days, and N-acetylcysteine for 3 days). The antioxidants abolished the responses of tumor necrosis factor- and interleukin-1ß, and the blunted the increase in interleukin-6. There was no change in either the percentage of monocytes producing cytokines or in their mean fluorescence intensity both before and after administration of the antioxidants. The authors conclude that oxidative stress is a major stimulus for the increased production of cytokines during inspiratory resistive breathing and that monocytes play no role in that process.
Diagnostic Studies
The American Thoracic Society and the European Respiratory Society (78) present a statement on respiratory muscle testing.
Structure and Histology
Ramirez-Sarmiento and coworkers (79) studied the effect of inspiratory muscle training on the structure of the inspiratory muscles in patients with COPD. Fourteen men (FEV1, 24% predicted) were randomized to true training or sham training. Training consisted of breathing through an inspiratory threshold device while generating 40 to 50% of maximum inspiratory pressure. The training was supervised and the sessions consisted of 30 minutes a day, 5 times a week, for 5 consecutive weeks. Training produced a 29% increase in maximal inspiratory pressure and 100% increase in inspiratory muscle endurance (the length of time that a patient was able to breathe against a load requiring the generation of 80% of maximal inspiratory pressure). Biopsies from the external intercostals muscles before and after training revealed a 38% increase in the proportion of type I fibers and a 21% increase in the size of type II fibers. Training had no effect on the structure of the vastus lateralis. The authors conclude that the improvement in inspiratory muscle strength and endurance after five weeks of supervised inspiratory muscle training is accompanied by increases in the proportion of type I fibers and the size of type II fibers. An editorial commentary by Levine and colleagues (80) accompanies this article.
Respiratory Muscle Involvement in Clinical Disorders
It has been generally believed that shortening of the diaphragm in hyperinflated patients with COPD is accompanied by a decrease in the contribution of the diaphragm to tidal breathing. Gorman and coworkers (81) used ultrasonography and magnetometry to measure diaphragmatic length at different lung volumes in 10 men with COPD (FEV1, 23% of predicted) and 10 control subjects. The length of the diaphragm was 20% shorter in the patients at residual volume and functional residual capacity, but length was similar to that of the control subjects at total lung capacity. The length of the zone of apposition was decreased by 50% at residual volume and functional residual capacity in the patients. At a given absolute lung volume, however, the length of the zone of apposition was greater in the patients. Although mean functional residual capacity was equivalent to predicted total lung capacity in the patients, tidal volume, tidal changes in the length of the zone of apposition and length of the diaphragm, and tidal volume displaced by the diaphragm were equivalent in the patients and in the control subjects. The authors conclude that, despite shortening of the diaphragm in patients with COPD, the motion and change in length of the diaphragm during tidal breathing is equivalent in patients with COPD and healthy subjects.
Phrenic nerve pacing has generally necessitated a thoracotomy. In a 35-year old man with a C2 spinal cord injury, DiMarco and coworkers (82) were able to stimulate the phrenic nerve by implanting electrodes into each hemidiaphragm via laparoscopic surgery. Bilateral pacing of the phrenic nerves produced an initial tidal volume of 420 ml. After a reconditioning program over 20 weeks, maximum stimulation produced an inspired volume of 1,120 ml. The patient was able to maintain full-time ventilator support with diaphragmatic pacing alone. The authors conclude that insertion of intramuscular electrodes into the diaphragm under laparoscopic surgery may prove to be a less invasive and less expensive alternative to conventional phrenic nerve pacing.
Hart and coworkers (83) subjected eight patients with bilateral diaphragmatic paralysis, eight patients with unilateral diaphragmatic paralysis, and eight healthy subjects to incremental treadmill exercise testing. Exercise time was 671 seconds in the control subjects, and reduced to 512 seconds in the patients with unilateral paralysis and to 456 seconds in the patients with bilateral paralysis. Peak minute ventilation was 114 liters per minute in the control subjects, and was reduced to 84 liters per minute in patients with unilateral paralysis and to 69 liters per minute in patients with bilateral paralysis. The ratio of peak oxygen consumption to peak minute ventilation was higher in both patient groups than in the healthy subjects. Five patients with unilateral paralysis and two patients with bilateral paralysis displayed decreased endurance while breathing against an inspiratory threshold load; exercise performance was decreased in this subgroup of patients as compared with patients who had normal endurance or with the healthy subjects. The authors conclude that exercise performance is impaired more than expected in patients with unilateral diaphragmatic paralysis and less than expected in patients with bilateral diaphragmatic paralysis.
| PULMONARY FUNCTION TESTING AND BRONCHOSCOPY |
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| TOP CONTENTS SLEEP-DISORDERED BREATHING CONTROL OF BREATHING RESPIRATORY MUSCLES PULMONARY FUNCTION TESTING AND... REFERENCES |
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To determine whether the best peak expiratory flow is flow limited and independent of effort, Tantucci and coworkers (85) studied six healthy subjects with and without the application of negative expiratory pressure (-10 cm H2O) at the mouth. FVC maneuvers were matched for expiratory effort measured with esophageal pressure (both the peak pressure and its maximal rate of rise). Application of negative expiratory pressure did not increase peak expiratory flow: 10.84 versus 10.82 liters per second. The authors conclude that best peak expiratory flow is flow limited and effort independent, and it reflects only lung and airway mechanics.
Ventilatory efficiency during exercise refers to the relationship between minute ventilation and metabolically produced CO2. In 474 healthy subjects (aged 17 to 78 years), Sun and coworkers (86) compared three mathematical expressions for quantifying ventilatory efficiency: the ratio of minute ventilation to CO2 output at the anaerobic threshold; the slope of minute ventilation to CO2 output below the compensatory point; and the lowest minute ventilation-to-CO2 output ratio during exercise. The new mathematical expression, the lowest minute ventilation-to-CO2 output ratio during exercise, was not significantly different from the ratio of minute ventilation to CO2 output at the anaerobic threshold and it was less variable than the slope of minute ventilation to CO2 output below the compensatory point. The new index was not affected by the site of testing, the ergometer, and the system used for measuring gas exchange. The regression equation for the lowest minute ventilation-to-CO2 output ratio was: 27.94 + 1.08 x age + (0.97 for females; 0.0 for males) – 0.0376 x height in centimeters. The authors conclude that a new mathematical expression, the lowest minute ventilation-to-CO2 output ratio during exercise, is the preferred method for assessing ventilatory inefficiency in adult patients.
Epidemiology Studies
To investigate the linkage between genetic markers and lung function, Joost and coworkers (87) did spirometry on 345 members of the Original Cohort and 1,233 members of the Offspring Cohort of the Framingham Study. A 10-cM genome-wide scan was performed on 1,578 members of 330 of the largest extended families in the Study. The loci most strongly influencing FEV1 and FVC colocalized on chromosomes 4, 6, and 21. FEV1 was most influenced by the locus on chromosome 6, and FVC was linked to markers on chromosome 21. The logarithms at odds favoring genetic linkage (LOD) were 2.4 for FEV1 and 2.6 for FVC. The authors conclude that the data from the Framingham Study identify a number of genetic loci that have a large influence on lung function.
To determine the influence of dietary intake and decline in lung function, McKeever and coworkers (88) studied a general population cohort in Nottingham, England. In a cross-sectional survey of 2,633 adults (aged 18 to 70 years), higher intakes of vitamin C and magnesium, but not of vitamins A or E, were associated with higher levels of FEV1. After 9 years, 1,346 of the individuals were again studied. Longitudinal analysis revealed that the decline in FEV1 over the 9 years was lower among subjects with higher average intake of vitamin C (by 50.8 ml per 100 mg of vitamin C per day), but was unrelated to magnesium intake. Decline in FEV1 was not related to intake of vitamins A or E. The authors conclude that a high dietary intake of Vitamin C may help reduce the rate of decline of lung function in adults.
To determine the influence of factors in early life on pulmonary function, Apostol and coworkers (89) analyzed data on 4,000 subjects enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Baseline measurements were obtained when the subjects were 18 to 30 years old, and measurements were repeated after 2, 5, and 10 years. After its peak, the change in FEV1 displayed a quadratic pattern until 40 years of age. The pattern varied with race and sex: FEV1 was higher in white subjects than in black subjects and higher in men than in women. Early initiation of smoking was associated with a faster rate of decline in FEV1. Prevalence of smoking was 28% when no family member smoked as compared with 59% when four or more family members smoked. Smoking by family members was associated with asthma in early life. The association between greater decline in FEV1 and smoking among family members may have arisen because the latter encouraged heavier smoking or starting to smoke at an earlier age. The rate of decline in FEV1 was 8.5% in never-smokers who were free of asthma, 10.1% in nonsmokers diagnosed with asthma, and 11.1% in baseline smokers who smoked at least 15 cigarettes a day. The combination of asthma and heavy smoking was synergistic, and associated with a rate of decline in FEV1 of 17.8%. The authors conclude that smoking among family members is associated with a more rapid decline in FEV1 and almost twice the risk of early asthma, and that the combination of smoking and asthma leads to a greater decline in FEV1 than either on its own.
In Diabetes Mellitus
Both the hydrostatic stress of chronic heart failure and thickening of the basal laminae associated with diabetes may damage the pulmonary alveolar–capillary membrane. To determine the effects of diabetes and treatment with insulin on lung diffusion in patients with congestive heart failure, Guazzi and coworkers (90) studied three patient groups and a control group (15 subjects in each). Carbon monoxide diffusing capacity was 101% of predicted in the control group, 87% of predicted in the patients with diabetes, 79% of predicted in the patients with heart failure, and 66% of predicted in the patients with both diabetes and heart failure. Insulin (10 IU) caused a 21% increase in diffusing capacity in the patients who had both heart failure and diabetes, a 10% increase in diffusing capacity in the patients who had diabetes alone, and no change in the patients with heart failure alone. The authors conclude that diffusing capacity is depressed in patients with diabetes and in patients with heart failure, the depression is greater in patients with a combination of the two disorders, and that insulin improves diffusing capacity in patients with diabetes but not in patients with heart failure.
Ciliary Function
The diagnosis of primary ciliary dyskinesia is based on the demonstration of ciliary defects, mainly concerning the dynein arms. Because the inner dynein arms exhibit low contrast on electron microscopy, they are difficult to see. Escudier and coworkers (91) studied the ciliary ultrastructure of 40 patients who had respiratory tract infections. Conventional transmission electron microscopy revealed normal cilia in 6 patients, confirmed a diagnosis of primary ciliary dyskinesia in 26 patients, and was inconclusive in 8 patients. All of the doubtful cases concerned the inner dynein arm. Conventional electron microscopy was able to define the ultrastructure of the inner dynein arms in 40.5% of the cases. Computed-assisted analysis of the images obtained by electron microscopy enhanced the signal-to-noise ratio, achieving a sensitivity of 100% and a specificity of 98%. The authors conclude that computer-assisted analysis of images obtained by conventional electronic microscopy enhances the visualization of the inner dynein arm of cilia.
Bronchoscopy
To characterize patient satisfaction with flexible bronchoscopy and to determine factors affecting willingness to undergo a repeat bronchoscopy, Lechtzin and coworkers (92) did a prospective study in a cohort of 481 patients. Over 80% of patients rated physicians as very good or excellent. Patients were less satisfied with the information they were provided about bronchoscopy, waiting time before and after bronchoscopy, and the environment. Most (71% definitely and 22% probably) of the patients would return for a repeat bronchoscopy if necessary. Factors associated with an increased willingness to return for a repeat bronchoscopy included better health status (odds ratio, 1.4), not being bothered by insertion of the bronchoscope (odds ratio, 2.0), better rating of the information provided (odds ratio, 1.2), and better rating of the physician (odds ratio, 1.1). The authors conclude that most patients are sufficiently satisfied with bronchoscopy to be willing to undergo a repeat procedure, and that four factors influence the willingness to undergo a repeat bronchoscopy: better health status, less discomfort during insertion of the bronchoscope, better information, and better rating of the physician. An editorial commentary by Mehta (93) accompanies this article.
Sackner (94) recalls the introduction of fiberoptic bronchoscopy as a medical procedure.
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| TOP CONTENTS SLEEP-DISORDERED BREATHING CONTROL OF BREATHING RESPIRATORY MUSCLES PULMONARY FUNCTION TESTING AND... REFERENCES |
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