Year in Review Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, and Pulmonary Function Testing in AJRCCM 2001 MARTIN J. TOBIN Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois
CONTENTS
SLEEP-DISORDERED BREATHING
Sleep Disordered Breathing (60) Epidemiology (9) Risk Factors (4) Pathophysiology (14) Cardiovascular Mechanisms (2) Upper Airway Mechanisms (8) Control of Breathing (4) Clinical Aspects (7) Upper Airway Resistance Syndrome (1) In Critically Ill Patients (1) In Children (4) Neuropsychological Function (1) Diagnostic Techniques (10) Treatment (15) Airway Pressure and Flow (10) Pharmacotherapy (2) Mandibular Devices (3) Review Article (1) Control of Breathing (11) Studies in Animals (7) Pathophysiologic Studies in Volunteers (2) Control of Breathing in Clinical Disorders (1) Dyspnea (1) Respiratory Muscles (19) Studies in Animals (8) Pathophysiologic Studies in Patients and Volunteers (7) Exercise (5) Contractility and Fatigue (2) Diagnostic Studies (1) Structure and Histology (2) Respiratory Muscle Involvement in Clinical Disorders (1) Pulmonary Function Testing and Bronchoscopy (15) Equipment and Techniques (5) Epidemiology Studies (7) In Acromegaly (1) In Mitochondrial Myopathy (1) Bronchoscopy (1)
Epidemiology
Supported by a Merit Review grant from the Veterans Affairs Research Service. Correspondence and requests for reprints should be addressed to Martin J. Tobin, M.D., Division of Pulmonary and Critical Care Medicine, Hines Veterans Affairs Hospital, Route 111N Hines, IL 60141. E-mail:
[email protected] Am J Respir Crit Care Med Vol 165. pp 584–597, 2002 DOI: 10.1164/rccm.2201061 Internet address: www.atsjournals.org
In 6,424 free-living individuals undergoing a single overnight polysomnography at home, Shahar and coworkers (1) examined the cross-sectional association between sleep-disordered breathing and self-reported cardiovascular disease. A total of 1,023 participants (16%) reported at least one manifestation of cardiovascular disease. The median apnea-hypopnea index was 4.4 (interquartile range, 1.3 to 11.0). Compared with the first quartile for the apnea-hypopnea index (0 to 1.3), the relative odds for cardiovascular disease were 0.98 for the second quartile (index of 1.4 to 4.4), 1.28 for the third quartile (index of 4.5 to 11), and 1.42 for the fourth quartile (index of greater than 11). The odds ratios for sleep-disordered breathing were 2.38 for heart failure, 1.58 for stroke, and 1.27 for coronary heart disease. The authors conclude that sleep-disordered breathing (with indexes considered normal or mildly elevated) has modest to moderate effects on manifestations of cardiovascular disease. An editorial commentary by Hedner and Grote (2) accompanies this article. To determine whether sleep-disordered breathing adversely affects the right heart, Guidry and coworkers (3) studied 180 subjects from the Framingham Heart Study who also participated in the Sleep Heart Health Study. On M-mode echocardiography, the wall of the right ventricle was thicker in 90 individuals with sleep-disordered breathing (respiratory disturbance index of 42) as compared with 90 individuals with a normal respiratory disturbance index: 0.78 versus 0.68 cm. This difference was not affected by obesity, hypertension, or pulmonary function. Dimensions of the right atrium and right ventricle, and systolic function of the right ventricle, did not differ between the groups. The authors conclude that individuals with sleep-disordered breathing develop right ventricular hypertrophy. An editorial commentary by Fishman (4) accompanies this article. To determine whether obstructive sleep apnea is associated with cardiac dysfunction independently of obesity, hypertension, and diabetes mellitus, Niroumand and coworkers (5) studied 533 subjects referred for possible sleep apnea. An apnea-hypopnea index of at least 5 per hour was found in 66%. Left-ventricular mass was correlated with body mass index, age, and hypertension in men, and with body mass index in women. Left-ventricular mass was not correlated with either apnea-hypopnea index or nocturnal oxygenation. After the exclusion of patients with hypertension and diabetes, the subjects with sleep apnea still had a 7% greater left-ventricular mass. Diastolic dysfunction of the left ventricle was correlated with age, but not with either apnea-hypopnea index or nocturnal oxygenation. The authors conclude that obstructive sleep
585
Year in Review
apnea is not associated with increased left-ventricular mass or impaired left-ventricular function independently of obesity, hypertension, or advancing age. To determine the prevalence of obstructive sleep apnea syndrome in the general population, Duran and coworkers (6) did a two-phase cross-sectional survey. The first phase consisted of an interview, blood pressure reading, and four-channel nocturnal polygraphy in 2,148 subjects. Habitual snoring was found in 35%, breathing pauses in 6%, and daytime hypersomnolence in 18% of the subjects. In the second phase, 390 subjects with suspected sleep apnea and 165 subjects judged to be normal underwent polysomnography in a laboratory. An apnea-hypopnea index of at least 10 was found in 19% of men and 15% of women. The odds ratio for sleep apnea increased 2.2-fold for each 10-year increase in age. After adjusting for several factors, apnea-hypopnea was associated with hypertension. The odds ratios for hypertension were 1.0 for an apnea-hypopnea index of 0, 2.47 for an index of 0.1 to 4.9, 1.30 for an index of 5.0 to 14.9, and 2.28 for an index exceeding 15.0. The authors conclude that the prevalence of sleep apnea is high in the general population, and that it increases with age and is associated with hypertension. Because the prevalence of sleep-disordered breathing has not been well defined in women, Bixler and coworkers (7) investigated the issue in a two-phase random sample from the general population. First, 12,219 women and 4,364 men, ranging in age from 20 to 100 years, were interviewed. Then, 1,000 women and 741 men were selected for one night of laboratory evaluation. The prevalence of sleep apnea (daytime symptoms and an apnea-hypopnea index of at least 10) was 3.9% in men and 1.2% in women. The prevalence was 0.6% in premenopausal women and 0.5% in postmenopausal women taking hormone therapy; sleep apnea was associated exclusively with obesity in these women. In postmenopausal women not taking hormone therapy, the prevalence of sleep apnea was 2.7%. The authors conclude that menopause is a significant risk factor for sleep apnea and that hormone replacement reduces the risk. An editorial commentary by Young (8) accompanies this article. To determine whether snoring and excessive daytime sleepiness contribute to accidents at work, Lindberg and coworkers (9) did a prospective population-based study over a period of 10 years. In 1984, 2,874 men, aged 30 to 64 years, completed a questionnaire on snoring and sleepiness. In 1994, 2,009 men (74% of the survivors) completed a follow-up questionnaire. Information on occupational accidents between 1984 and 1994 were obtained from the Swedish registry. A total of 345 occupational accidents were reported by 247 of the men (12% of those in the follow-up survey). After adjusting for age, body mass index, smoking, alcohol dependence, years of work, type of job, and other factors, men who reported both snoring and excessive daytime sleepiness at baseline had a 2.2-fold greater risk of occupational accidents over the subsequent 10 years. An increased risk was not seen for either snoring without daytime sleepiness or for daytime sleepiness without snoring. The authors conclude that men with both snoring and excessive daytime sleepiness have a more than two-fold increase in the risk of occupational accidents. Risk Factors
To determine the extent to which snoring and excessive daytime sleepiness are influenced by genetic factors, Carmelli and coworkers (10) studied 1,560 male-male twin pairs (818 monozygotic and 742 dizygotic) aged 74 years. In the sample, 26% were habitual snorers, 18% had excessive daytime sleepiness, and 29% were obese. Modeling analysis revealed that genetic factors accounted for 64% of the variance in obesity, 40% of
the variance in daytime sleepiness, and 23% of the variance in self-reported snoring. Only 30% of the variance in snoring was explained by the genetic variance for obesity. The authors conclude that self-reported symptoms of snoring and daytime sleepiness in older men have a genetic basis that is largely independent of the genetic variance for obesity. To determine the adverse effect of sleep-disordered breathing in patients with coronary artery disease, Mooe and coworkers (11) prospectively followed 408 patients with coronary disease (verified by angiography) for 5 years. A composite of death, cerebrovascular events, and myocardial infarction was increased by 62% in patients who had an apnea-hypopnea index of at least 10, and the composite was increased by 70% in patients who had an oxygen desaturation index of at least 5. After adjusting for other risk factors, sleep-disordered breathing was associated with an almost 3-fold increased risk of cerebrovascular accidents. The authors conclude that sleep-disordered breathing in patients with coronary artery disease is associated with a worse prognosis and is independently associated with cerebrovascular accidents. Studies using cephalometry have shown that measures of the cranial and facial form are linked to obstructive sleep apnea. To determine whether simple measures made with anthropometric calipers would discriminate between subjects with and without sleep apnea, Cakirer and coworkers (12) studied 364 white and 165 African-American individuals. Among whites, subjects with an apnea-hypopnea index of at least 15 had a 2% greater cranial index and a 3% smaller facial index as compared with subjects who had an apnea-hypopnea index of less than 5. Neither index was related to apnea-hypopnea index in the African Americans. Among subjects with sleep apnea, the cranial index was 3% greater and the facial index was 5% smaller in whites as compared with African Americans. The authors conclude that brachycephaly is associated with sleep apnea in whites but not in African Americans. The absence of leptin in the C57BL/6J-Lepob mouse induces profound obesity, respiratory depression, and hypercapnia. Polotsky and coworkers (13) investigated the interrelationship between leptin and sex in mice. Compared with wild-type C57BL/6J mice of normal body weight and wild-type C57BL/6J mice with diet-induced obesity, both male and female C57BL/ 6J-Lepob mice with leptin deficiency and obesity had a decrease in the ventilatory response to hypercapnia. Female mice with leptin deficiency had a lower hypercapnic ventilatory response and a lower respiratory drive during both non-REM (rapid eye movement) sleep and wakefulness, as compared with male mice with leptin deficiency. The hypercapnic ventilatory response was equivalent in the male and female wild-type mice during wakefulness and non-REM sleep, but lower in the female mice during REM sleep. The authors conclude that leptin deficiency has a more detrimental effect on the ventilatory sensitivity to hypercapnia during wakefulness and non-REM sleep in female than in male obese mice. Pathophysiology
Cardiovascular mechanisms. When doing spectral analysis of heart rate variability to assess autonomic function, the use of an algorithm that minimizes the influence of breathing enhances the accuracy of the analysis. In 13 men with obstructive sleep apnea (apnea-hypopnea index exceeding 20), Khoo and coworkers (14) did conventional and modified spectral analyses both before and after 3 to 9 months of therapy with continuous positive airway pressure (CPAP). Indices derived from conventional power-spectral analysis, namely, the power in the high-frequency range (0.15 to 0.4 Hz) and in the low-frequency range (0.04 to 0.15 Hz), did not change with CPAP. A
586
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
modified index, the average transfer gain, relating breathing to the changes in the R-R interval on the ECG, increased after CPAP in both the supine and standing position. The increase in the modified index, which reflects enhanced vagal control over the heart rate, was proportional to the recorded compliance in the use of CPAP. Another index, the modified ratio of low-frequency power to high-frequency power, decreased in proportion to use of CPAP. The change in this index reflects a decrease in sympathetic activity. The authors conclude that CPAP improves cardiac autonomic function and that the improvement is proportional to compliance in the use of CPAP. In a state of the art review article, Leung and Bradley (15) discuss the association between sleep apnea and cardiovascular disease. Upper airway mechanisms. To determine the factors that influence the quality of sleep in space, Elliott and coworkers (16) studied five healthy subjects before, during, and after space flight. Each subject underwent four full polysomnograms during a 9-day or 16-day space shuttle mission. Microgravity decreased the apnea-hypopnea index from 8.3 to 3.4 events per hour. Snoring was virtually eliminated, decreasing from 17% of total sleep time before flight to 0.7% during flight. Arousals decreased by 19%, and almost entirely because of a decrease in respiratoryrelated events. Shortly after returning to earth, the variables returned to the preflight values. The authors conclude that microgravity decreases sleep-disordered breathing, and that gravity plays a dominant role in the increase in upper airway resistance that occurs during sleep. An editorial commentary by Dinges (17) accompanies this article. During wakefulness, the greater activity of the dilator muscles of the pharynx in patients with obstructive sleep apnea, as compared with healthy subjects, represents a mechanism of compensation for a collapsible airway. In 10 patients with obstructive apneas (respiratory disturbance index of at least 25) and 12 healthy subjects, Fogel and coworkers (18) determined the relationship between activity of the genioglossus muscle and negative pressure in the epiglottis while inducing a wide range of epiglottic pressures. The wide range in pressures was achieved through use of basal breathing, resistive loading, helium-oxygen mixtures, and an iron lung. Under all conditions, the tonic, phasic, and peak phasic activity of the genioglossal electromyogram was about twice as great in the patients as in the control subjects. The patients also generated more negative excursions in epiglottic pressure. The relationship between genioglossal activity and epiglottic pressure was tight under all conditions in both the patients and the control subjects (correlation coefficients of 0.69 to 0.91), and the slope of the relationship did not differ between the patients and the control subjects. The authors conclude that patients with sleep apnea display increased genioglossal activity during wakefulness because of a combination of increased tonic activity of the genioglossal muscle and the generation of more negative pressure during inspiration. An editorial commentary by Remmers (19) accompanies this article. Because impaired sensation in the upper airway may predispose to apneas of longer duration, Kimoff and coworkers (20) studied upper airway sensation in 37 patients with obstructive sleep apnea (apnea-hypopnea index, 39 per hour), 12 snorers without apneas, and 15 healthy subjects. Compared with the control subjects, both the patients and the snorers had about a one-third reduction in two-point discrimination in the oropharynx. The vibratory threshold in the upper airway was 82% higher in the patients and 73% higher in the snorers than in the control subjects. The three groups had equivalent two-point discrimination and vibratory threshold at the hand and lip. Twenty-three patients treated with CPAP for six
VOL 165
2002
months experienced a 14% decrease in the vibratory threshold in the upper airway; two-point discrimination did not change. The authors conclude that both patients with sleep apnea and snorers have a selective impairment in detecting mechanical stimuli in the upper airway, and that this impairment is partly reversible with CPAP. An editorial commentary by Svanborg (21) accompanies this article. In 18 children aged 2 to 9 years with obstructive sleep apnea (apnea-hypopnea index 11.2), Arens and coworkers (22) assessed the structure of the upper airway using magnetic resonance imaging under sedation. Compared with control subjects, the volume of the upper airway was 40% smaller, the adenoids 55% larger, and the tonsils 57% larger in the patients. The volume of the mandible and tongue were similar in the two groups. The apnea-hypopnea index was correlated with the volume of the tonsils and adenoids (r 0.51). The authors conclude that the upper airway is smaller in children with obstructive sleep apnea because the adenoids, tonsils, and soft palate are enlarged. To determine the effect of activity of the pharyngeal muscles on the pharynx, Kuna (23) did bronchoscopy and computer-based planimetry in decerebrate cats. Stimulation of the cut ends of the medial and lateral branches of the hypoglossal nerve, which supply motor output to the tongue protruder and retractor muscles, caused the greatest increase in the area in the rostral oropharyngeal airway, although the area of the caudal oropharynx also increased. Stimulation of the glossopharyngeal nerve, which supplies motor output to several pharyngeal muscles, including the stylopharyngeus and levator veli palatini, dilated the velopharynx and oropharynx at the rim of the soft palate. Stimulation of the pharyngeal branch of the vagus, which supplies motor output to the pharyngeal constrictor muscles, constricted the airway at the level of the soft palate but did not change the area of the rostral oropharynx. The author concludes that the mechanical effects that result from contraction of the pharyngeal muscles depend on the level of the airway and the particular muscle being activated. Control of breathing. The reason for the wide variation in the severity of obstructive sleep apnea is not known. To determine the role of ventilatory stability and controller gain, Younes and coworkers (24) studied 12 patients with severe disease (apnea-hypopnea index 88) and 20 patients with mild-to-moderate disease (apnea-hypopnea index 27) during sleep. To remove the confounding influence of upper airway resistance, the upper airway was first stabilized with CPAP. Controller gain in a patient was measured by gradually increasing the level of proportional assist ventilation. The gain was taken as the ratio of the tidal volume during assisted breathing to the tidal volume of the first reloaded (unassisted) breath. Periodic breathing with central apneas occurred in 75% of patients with severe sleep apnea and in 30% of patients with mild-tomoderate sleep apnea despite the level of assistance being 42% higher in the mild-to-moderate group. The authors conclude that the chemical control system is unstable in patients with severe obstructive sleep apnea, and that the increase in controller gain makes patients more susceptible to repetitive cycling of ventilation. An editorial commentary by Khoo (25) accompanies this article. The role of nonchemical neuromechanical influences in causing apnea following mechanical ventilation is debated by Dempsey and Skatrud (26) and Younes (27), with rebuttals from each (28, 29). Clinical Aspects
Upper airway resistance syndrome. Guilleminault and coworkers (30) studied the frequency of hypotension in 4,409 subjects
587
Year in Review
referred for overnight polysomnography. Hypotension, defined as a systolic pressure of less than 105 mm Hg and a diastolic pressure of less than 65 mm Hg, was found in 101 subjects (2.3%). Hypotension was more prevalent in subjects with the upper airway resistance syndrome (23%), as compared with subjects with obstructive sleep apnea (0.1%), parasomnia (0.7%), restless legs (0.9%), or insomnia (0.9%). When tilted from the supine to the erect position, 15 subjects with orthostatic intolerance and the upper airway resistance syndrome experienced a 27 mm Hg drop in systolic pressure, as compared with a drop of less than 8 mm Hg in both the healthy subjects and the subjects with obstructive sleep apnea. Compared with 15 healthy subjects, 24-hour ambulatory monitoring in the 15 subjects with upper airway resistance syndrome revealed lower daytime systolic pressure (119 versus 131 mm Hg) and lower daytime diastolic pressure (75 versus 86 mm Hg). The authors conclude that more than a fifth of subjects with upper airway resistance syndrome have low blood pressure and complain of orthostatic intolerance. In critically ill patients. To characterize the pattern of sleep in critically ill patients, and particularly the effect of noise, Freedman and colleagues (31) did continuous polysomnography for 24 to 48 hours in 22 patients (20 were receiving mechanical ventilation). The EEG could not be scored in five patients because of septic encephalopathy. Total sleep time was 8.8 hours (range, 1.7 to 19.4 hours) over a day. All patients had abnormal sleep architecture, each bout of sleep averaged 15 minutes (range 6–40), and stage 1 sleep predominated (59%). Total sleep time was longer during the day than at night (57 versus 43%). Environmental noise was responsible for only 12% of arousals. The authors conclude that mechanically ventilated patients are qualitatively, but not quantitatively, sleep deprived, and that environmental noise accounts for a smaller proportion of the sleep-wake abnormalities than is generally imagined. In children. Obstructive sleep apnea has been noted in 30 to 60% of subjects with Down’s syndrome and is attributed to anatomic factors. To determine whether the syndrome itself is associated with structural abnormalities, Uong and coworkers (32) did magnetic resonance imaging in 11 children (mean age 3 years) with Down’s syndrome without sleep apnea. Compared with healthy subjects, the children with Down’s syndrome had a 39% decrease in airway volume, smaller mid and lower face skeleton, and a 50% decrease in adenoidal and tonsillar volume. The tongue, soft palate, pterygoid muscles, and parapharyngeal fat pads were similar in the two groups. The authors conclude that children with Down’s syndrome without sleep apnea have a smaller upper airway as compared with healthy children, as a result of soft tissue crowding within the boundaries of a smaller midface and lower face skeleton. To determine whether the distribution of sleep disordered breathing in infants who die from sudden infant death syndrome (SIDS ) varies with age and sex, Kato and coworkers (33) studied 40 infants who subsequently died from SIDS and 607 healthy infants, aged 2 to 19 weeks. At 4 to 8 weeks of age, 71% of 14 infants who died from SIDS had mixed apneas, as compared with 31% of healthy infants. The SIDS infants had twice the number of obstructive apneas and 50% more mixed apneas as compared with the healthy infants. At 9 to 19 weeks, 77% of 26 SIDS infants had obstructive apneas as compared with 41% of 540 healthy infants. Compared with the healthy infants, the SIDS infants had 50% more obstructive apneas and double the number of mixed apneas. The frequency of apneas was greater in male infants. The frequency of apneas decreased with age, and the decrease was greater in the healthy infants. The authors conclude that infants who subsequently
die from SIDS have frequent apneic episodes during sleep, a smaller decrease in the frequency of apneas with age, and are more likely to be male, as compared with healthy infants. In a state of the art review article, Hunt (34) discusses the mechanisms, risks, and diagnosis of sudden infant death syndrome (SIDS). In a state of the art review article, Marcus (35) discusses sleep-disordered breathing in children. Neuropsychological function. To determine the relationship between neuropsychological function and sleep-disordered breathing, Adams and coworkers (36) studied 100 subjects with a median apnea-hypopnea index of 14. Apnea-hypopnea index and/or hypoxemia predicted three neuropsychological constructs: declarative memory (retrieval of acquired information after a delay), working memory (ability to hold information in awareness and use it to guide behavior), and signal discrimination (ability to discriminate among rapidly changing signals). Sleep-disordered breathing accounted for 4–6% of the variance in these constructs, having a dose-dependent effect. Sleepiness was the best predictor of vigilance. The authors conclude that sleep-disordered breathing has a negative and dose-dependent effect on neuropsychological functions, and, apart from vigilance, the effects are not related to sleepiness. Diagnostic Techniques
Thermistors cannot accurately track changes in flow, and recordings of pressure at the nasal aperture have been used as a monitoring tool. Because nasal pressure is not linearly related to flow, Farre and coworkers (37) examined the influence of this nonlinearity on the detection of respiratory events. In six patients undergoing CPAP titration for severe sleep apnea, flow was recorded with a pneumotachograph. The flow signals, including flow-limited events, were reproduced by a flow generator connected to an analog of the nares. Pressure at the nasal aperture displayed considerable error in classifying both flow limitation and flow amplitude during a hypopnea. Linearizing the pressure signal, by computing its square root, produced signals that closely mirrored those from the pneumotachograph: flow amplitude (r2 0.98) and flow limitation (r2 0.99). The authors conclude that computing the square root of nasal pressure linearizes the signal and accurately quantifies hypopneas and the degree of inspiratory flow limitation. Monitoring the pressure at the nasal aperture is a promising method for detecting hypopneas. To assess the accuracy of this method against a reference standard of flow, measured with a pneumotachograph attached to a nasal mask, Thurnheer and coworkers (38) studied 20 patients with an apnea-hypopnea index of 24 events per hour. Compared with the nasal pneumotachograph, the bias and limits of agreement (mean difference 2 SD) for the apnea-hypopnea index derived from nasal pressure was 3.9 4.6 events per hour. Accuracy was not affected by the patients’ own rating of the degree of nasal obstruction. When the apnea-hypopnea index was based on the square root of the nasal pressure signal, the bias and limits of agreement was 0.9 9.0 events per hour. The square root of the pressure signal closely tracked the flow signal measured with the nasal pneumotachograph over a series of 10 breaths (r2 of 0.88 to 0.96), but the relationship was highly variable over the entire night. The authors conclude that measuring pressure at the nasal aperture provides a reliable estimate of the apnea-hypopnea index, and that a square-root transformation of the signal improves the accuracy over short-term, but is not an advantage for recordings throughout the night. In 15 patients with moderate sleep apnea (apnea-hypopnea index 30), Cracowski and coworkers (39) classified 1,061 events that caused partial airway obstruction but did not cause
588
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
a complete apnea. Eighty percent of the events consisted of obstructive hypopneas, defined as either a decrease in flow of at least 50% or a decrease in flow of at least 30% combined with a 3% fall in oxygen saturation or a cortical arousal. Of events associated with a 30 to 50% decrease in flow, arousal occurred in 63% and the events were thus classified as obstructive hypopneas. Arousals related to respiratory effort, defined as a decrease in flow of less than 30% combined with an arousal, represented only 5% of the nonapneic events. Fifteen percent of events were indeterminate, falling between the criteria for classification. Swings in esophageal pressure were equivalent at the termination of obstructive hypopneas and arousals related to respiratory effort (22 versus 19 cm H2O). The authors conclude that obstructive hypopneas account for 80% of nonapneic respiratory events and that arousals related to respiratory effort account for only 5%. Because of the logistical problems associated with polysomnography, Gurubhagavatula and coworkers (40) assessed the accuracy of a risk-stratification algorithm for separately identifying subjects without sleep apnea and subjects with severe apneas (at least 30 events per hour). The algorithm consisted of a questionnaire with or without nocturnal oximetry, and was compared against polysomnography in 359 subjects. Among subjects without sleep apnea, the algorithm had a sensitivity of 95%, and the missed cases had mild disease. Because the high prevalence of sleep apnea among referred subjects is high, the algorithm would decrease the number of ordered sleep studies by only 8 to 12%. The algorithm identified subjects with severe sleep apnea with a specificity of 97%; as a result, up to 23% of subjects were prioritized to receive an early sleep study. The authors conclude that a risk-stratification strategy based on a questionnaire and nocturnal pulse oximetry identifies few subjects not needing a sleep study, but identifies a larger proportion of subjects needing an early sleep study because of severe disease. In 137 patients undergoing polysomnography, Hosselet and coworkers (41) compared several indices for predicting symptoms of excessive daytime sleepiness. Threshold values for each index were first defined in 34 randomly selected subjects. A composite index based on the total number of apneas, hypopneas, and flow limitation (on a flow-time tracing), without regard for desaturation, was the best discriminator. The discriminating threshold value was then prospectively tested in the remaining 103 subjects (68 of whom had excessive daytime sleepiness). A threshold of more than 18 events per hour on the composite index had a sensitivity of 71% and a specificity of 60% for identifying subjects with excessive daytime sleepiness. The authors conclude that a composite index that includes apneas, hypopneas, and events defined by flow limitation is superior to other indices in predicting symptoms of excessive daytime sleepiness. Measurement of daytime sleepiness with the multiple sleep latency test or the maintenance of wakefulness test involves several hours of electrophysiologic recordings, the reading of which requires considerable skill. The OSLER test is a behavioral test lasting no more than 40 minutes. The subject presses a button in response to a light flashing for a second every three seconds; the test is terminated if the subject misses seven consecutive flashes, because he is assumed to have slept for 21 seconds. In 10 healthy subjects, Priest and coworkers (42) found that the OSLER test was shorter on a day after sleep deprivation as compared with a day after usual sleep (25 versus 38 minutes). Sleep episodes of at least 3-second duration were almost always present when the subjects missed four or more consecutive flashes. The sensitivity of the OSLER test in detecting sleep was 85% and its specificity was 94%. The au-
VOL 165
2002
thors conclude that the OSLER test is a reliable method for detecting daytime somnolence, with advantages of simplicity, low cost, automatic reading, and little demand on technical personnel. An editorial commentary by Bliwise (43) accompanies this article. To determine whether incidental periodic leg movements during sleep contribute to daytime sleepiness, Chervin (44) analyzed data from 1,124 patients with suspected sleep-disordered breathing (84% of whom had an apnea-hypopnea index exceeding 5). Increased leg movements were associated with a decrease in objective measures of daytime sleepiness, although the movements explained less than 1% of the variance. Leg movements combined with arousals were also associated with less daytime sleepiness. The authors conclude that incidental periodic leg movements during sleep are not associated with excessive daytime sleepiness. The importance of assessing leg movement in an overnight sleep study is debated by Walters (45) and Mahowald (46), with rebuttals from each (47, 48). In a clinical commentary, Douglas (49) discusses the diagnosis and management of non-respiratory causes of sleepiness. Treatment
Airway pressure and flow. Montserrat and coworkers (50) developed a sham CPAP machine that mimics true CPAP, in terms of noise, gas flow, need for a mask and other constraints. The machine, however, does not deliver pressure. Sham CPAP was compared with true CPAP in 45 patients with sleep apnea (apnea-hypopnea index 54) using a doubleblind randomized design. Optimal CPAP produced a decrease in both sleepiness on the Epworth scale and other symptoms of sleep apnea to one-quarter of the values experienced with sham CPAP. Optimal CPAP improved vigilance 2.5 times and general productivity 8 times. The two groups had equivalent compliance: about 4.4 hours per night. The authors conclude that CPAP is effective in relieving symptoms in patients with moderate-to-severe sleep apnea. In 142 patients with mild sleep apnea (apnea-hypopnea index 10 to 30), Monasterio and coworkers (51) did a randomized controlled trial of conservative therapy (sleep hygiene and weight loss) versus conservative therapy plus CPAP. Patients receiving CPAP experienced a 33% decrease in symptoms related to sleep apnea at both three and six months, whereas no change occurred in the patients treated conservatively. Improvement in functional outcome on a sleep questionnaire approached significance in the CPAP group. CPAP did not produce a significant decrease in sleepiness on the Epworth scale. Compliance with CPAP was 4.8 hours, and 62% of the patients continued its use at the end of the study. The authors conclude that CPAP provides relief from some but not all symptoms in patients with mild sleep apnea. To determine whether CPAP improves sleep quality, McArdle and Douglas (52) did a randomized controlled trial of CPAP versus a placebo capsule in 22 patients with sleep apnea syndrome (apnea-hypopnea index, 40 per hour). Compared with placebo, one month of CPAP decreased the arousal index (21 versus 45 events per hour), increased the duration of Stage 3/4 sleep (41 versus 23 minutes), increased REM sleep (86 versus 74 minutes), and decreased Stage 1 sleep (12 versus 24 minutes). A decrease in sleepiness on the Epworth scale after 6 to 12 months of CPAP was correlated with sleep efficiency (r 0.78), REM sleep (r 0.55), Stage 3/4 sleep (r 0.50), and arousal index (r 0.43). The authors conclude that one month of CPAP improves sleep quality in patients with sleep apnea and that the benefit is associated with a decrease in daytime sleepiness at 6 to 12 months.
Year in Review
In 68 patients with a median apnea-hypopnea index of 35, Faccenda and coworkers (53) did a randomized crossover comparison of CPAP versus a placebo capsule (each for four weeks). CPAP produced a small decrease in 24-hour diastolic blood pressure (77.8 versus 79.2 mm Hg), with the greatest fall occurring between 2:00 A.M. and 10:00 A.M. The fall in diastolic pressure was greater in two a priori defined subgroups: in those using CPAP for more than 3.5 hours per night (79.6 versus 81.5 mm Hg); and in patients experiencing more than 20 desaturations per hour (77.4 versus 82.4 mm Hg). The frequency of desaturation was the best predictor of diastolic pressure. The authors conclude that CPAP can produce a small decrease in blood pressure in patients with sleep apnea, especially in those with oxygen desaturation. An editorial commentary by Karlawish and Pack (54) accompanies this article. To determine whether nasal CPAP improves neuropsychological function, Henke and coworkers (55) did a double-blind trial in 46 patients with sleep apnea. Therapeutic levels of CPAP produced improvement in multiple measures of neuropsychological function, but the changes were not different from those occurring with subtherapeutic CPAP (less than 1 cm H2O). The authors conclude that it is feasible and important to include a placebo control when studying therapy directed at neuropsychological function in patients with sleep apnea. An autoadjusting CPAP system alters the level of delivered pressure based on the measurement of upper airway impedance. In 52 patients with an apnea-hypopnea index of 35, Randerath and coworkers (56) did a randomized crossover comparison of standard (constant) CPAP and an autoadjusting system (six weeks of each). Both systems decreased the apneahypopnea index to about 5, but the mean pressure was lower for the autoadjusting system as compared with constant CPAP (5.7 versus 7.8 cm H2O). The pressure was lower with the autoadjusting system for 82% of the study period, and 75% of patients preferred this system. The authors conclude that an autoadjusting CPAP system is as effective as standard CPAP in treating sleep apnea despite delivering a lower airway pressure. An editorial commentary by Levy and Pepin (57) accompanies this article. Adaptive servo-ventilation is designed to suppress CheyneStokes respiration without causing over-ventilation. The patient’s ventilation is servo-controlled to achieve a moving target of 90% of the average minute ventilation. In 14 patients with cardiac failure, Teschler and coworkers (58) did a randomized comparison of four treatments: nasal oxygen at 2 liters per minute, CPAP (mean, 9.3 cm H2O), bilevel airway pressure (inspiration 14 cm H2O, expiration 5 cm H2O), and adaptive servo ventilation (operating mostly at the default setting of 7 to 9 cm H2O). The apnea-hypopnea index was 45 without treatment. The index fell to 28 with oxygen, to 27 with CPAP, to 15 with bilevel pressure, and to 6 with adaptive servo-ventilation. The arousal index was 65 without treatment. The index fell to 30 with oxygen, to 30 with CPAP, to 16 with bilevel pressure, and to 15 with adaptive servo-ventilation. Slow wave sleep combined with REM sleep increased from 26 to 43% of total sleep time with adaptive servo-ventilation. The authors conclude that one night of adaptive servoventilation improves nocturnal breathing and sleep quality in patients with heart failure and Cheyne-Stokes respiration. In 13 adult patients with cystic fibrosis (mean age 26 years), Milross and coworkers (59) compared the effects of low-flow oxygen, non-invasive positive pressure ventilation (inspiratory pressure 12 cm H2O, expiratory pressure 5 cm H2O), and air breathing during three nights of sleep. Minute ventilation did not change between wakefulness and non-REM sleep on any night. Minute ventilation decreased between non-REM and
589
REM sleep on the night with air breathing (by 1.43 liters per minute) and on the night with low-flow oxygen (by 1.88 liters per minute). Noninvasive ventilation prevented the fall in minute ventilation between non-REM and REM sleep. Oxygen saturation was improved by both low-flow oxygen and noninvasive ventilation, and noninvasive ventilation prevented the increase in PCO2 seen on the other two nights. The authors conclude that noninvasive ventilation improves alveolar ventilation in patients with cystic fibrosis during sleep. Pharmacotherapy. Modafinil is a new wake-promoting agent that is effective in patients with narcolepsy. To determine its effect on residual sleepiness in patients with obstructive sleep apnea being treated with CPAP, Pack and coworkers (60) did a double-blind trial in 157 patients. All of the patients had increased daytime sleepiness (score of at least 10 on the Epworth scale), and 45% had severe sleepiness (scores of at least 15). Within one week, modafinil produced a 29% decrease in the score for daytime sleepiness. The score was normalized (less than 10) in 51% of the modafinil group, as compared with 27% of the placebo group. At four weeks, the time for sleep latency was increased by 16%. Treated patients had a two-fold increase in headaches and a four-fold increase in nervousness, as compared with placebo. Usage of CPAP did not change. The authors conclude that modafinil reduces residual daytime sleepiness in patients with sleep apnea being treated with CPAP. In 30 patients with sleep apnea who continued to receive nasal CPAP, Kingshott and coworkers (61) did a double-blind crossover study of modafinil (400 mg) and placebo (each for 2 weeks). Modafinil had no effect on sleepiness (Epworth scale or multiple sleep latency test), but it produced a 9% improvement in alertness (maintenance of wakefulness test). Modafinil did not alter cognitive performance or the quality of life, but it produced a 3% decrease in the hours of CPAP at night. The authors conclude that modafinil improves some aspects of alertness in patients with sleep apnea, but it is not clear whether the benefit is sufficient to justify its use in clinical practice. Mandibular devices. In 28 patients with sleep apnea (apnea-hypopnea index 30), Mehta and coworkers (62) did a randomized placebo-controlled crossover trial of an anterior mandibular positioner. The device was custom made from dental impressions, and was advanced incrementally during an acclimatization period until resolution of symptoms, or to the maximum tolerated. The device produced complete resolution of sleep-disordered breathing (apnea-hypopnea index less than 5) in 38%, and partial resolution (decrease in apneahypopnea index of at least 50% but still greater than 5 per hour) in 25% of the patients. Compared with placebo (a control oval plate), the device produced a decrease in apneahypopnea index from 30 to 14, improvement in minimum oxygen saturation from 87 to 91%, and a decrease in arousals from 41 to 27 per hour. Subjective improvement was reported by 96% of the patients. Four factors predicted success: neck circumference, baseline apnea-hypopnea index, and two cephalometric variables. The authors conclude that an anterior mandibular positioner is effective in treating some patients with obstructive sleep apnea. An editorial commentary by Ferguson (63) accompanies this article. To assess side effects associated with use of an oral appliance that advances the mandible, Fritsch and coworkers (64) studied 22 patients with obstructive sleep apnea (apnea-hypopnea index 28) before and after using the appliance for at least 1 year. Polysomnography showed a persistent reduction in the apnea-hypopnea index (6 events per hour) at 3 to 12 months. Sleepiness on the Epworth scale was decreased by 33% at 3 to
590
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
12 months and by 38% at 12 to 30 months. Side effects included mucosal dryness (86% of patients), tooth discomfort (59% of patients), and hypersalivation (55% of patients), but patients regarded these as mild and none required the discontinuation of the appliance. Cephalometry revealed small (less than 1 mm) but significant reductions in dental overbite and overjet. The authors conclude that patients using oral appliances for advancing the mandible commonly experience side effects of a mild nature and that the therapy provides a sustained reduction in apnea-hypopnea events. Review Article
In an occasional essay, Pack (65) argues that academic programs in pulmonary medicine have undervalued the research done on sleep and neurobiology.
CONTROL OF BREATHING Studies of Animals
The obese Zucker rat exhibits depressed serotonergic activity in the central nervous system, which is linked to overeating. To determine the role of serotonin on control of breathing, Nakano and coworkers (66) gave ritanserin, a selective antagonist of the serotonin 2A and 2C receptor, to four groups of awake Zucker rats: young (6–8 weeks) lean; young obese; older (7–8 months) lean; and older obese. The pattern of breathing was more rapid and shallow in older obese rats as compared with the older lean rats. Ritanserin caused a 12% decrease in minute ventilation, a 9% decrease in respiratory rate, and an 11% increase in oxygen consumption. Ritanserin had little effect on ventilation in the other three groups, nor did it influence the ventilatory responses to hypoxia or hypercapnia in any group. In the older rats, the critical pressure in the isolated pharynx was greater in the obese as compared with the lean rats, indicating greater collapsibility. Ritanserin increased the critical pressure in both the obese and lean older rats, indicating an increase in collapsibility. The authors conclude that the 2A and 2C serotonin subtype contributes to normal breathing and the maintenance of a stable upper airway in obese Zucker rats, and that augmented serotonergic drive to the dilator muscles of the upper airway may prevent its collapse. An editorial commentary by Veasey (67) accompanies this article. Nakano and coworkers (68) asked, “Is blunting of the thermoregulatory and ventilatory responses to hypoxia in obese Zucker rats caused by decreased activity of nitric oxide synthase in the brain?” In response to hypoxia, the lean rats developed an abrupt increase in minute ventilation followed by a gradual decline. The obese rats also developed an abrupt increase in ventilation, and it remained flat as the hypoxia was sustained. Hypoxia induced a greater drop in body temperature and oxygen consumption in the lean rats as compared with the obese rats. In the lean rats, intraperitoneal administration of NG-nitro-L-arginine methyl ester (L-NAME), a nonspecific inhibitor of nitric oxide synthase, caused a decrease in temperature of about 0.2 C, and administration of 7-nitroindazole, a selective inhibitor of neuronal nitric oxide synthase, caused a decrease in temperature of 1.1 C; temperature did not change in the obese rats. Both inhibitors attenuated the hypothermia and hypometabolism induced by hypoxia in the lean rats, but not in the obese rats. Both inhibitors markedly decreased minute ventilation during air and hypoxia in the lean rats, but not in the obese rats. The authors conclude that the blunted thermoregulatory and ventilatory responses to hypoxia in obese Zucker rats result from decreased activity of nitric oxide synthase in the central nervous system.
VOL 165
2002
To determine the relationship between respiratory center depression and insulin-dependent diabetes mellitus, Polotsky and coworkers (69) studied two mouse models: C57BL/6J mice with streptozotocin-induced diabetes who ate a regular or an obesity-inducing diet; and non-obese Ltj mice that develop diabetes spontaneously. In both models, the development of insulin-dependent diabetes caused depression of the ventilatory response to hypercapnia. The response was related to the duration of hyperglycema (r 0.79), and was not associated with decreases in plasma insulin or leptin. All 14 of the C57BLl/6J obese mice developed diabetic ketoacidosis, but only six hyperventilated; the increase in minute ventilation was correlated with the increase in plasma leptin (r 0.77). Leptin-deficient mice had low levels of minute ventilation and ketones. The authors conclude that depression of the ventilatory response to hypercapnia is related to the duration of hypercapnia but not to serum leptin, whereas the hyperventilation of diabetic ketoacidosis is related to leptin. To assess whether intracellular acidification is sufficient to produce central chemosensitivity, Kiwull-Schone and coworkers (70) studied anesthetized, paralyzed, vagotomized, and mechanically ventilated rabbits. Intravenous administration of S8218, an inhibitor of the sodium-hydrogen ion exchange type 3, produced a 51% increase in respiratory drive, measured as the product of integrated burst amplitude of the phrenic nerve and respiratory frequency. Despite no change in the state of metabolic acid-base, the inhibitor decreased the carbon dioxide apneic threshold by 3.3 mm Hg. As a result, marked hyperventilation failed to abolish phrenic nerve rhythmicity in four of seven rabbits. The authors conclude that inhibition of the sodium-hydrogen ion exchanger acts on the respiratory center output in the same manner as hypercapnia, suggesting that intracellular acidification is a sufficient signal for central CO2 chemosensitivity. In anesthetized spontaneously breathing rabbits, KiwullSchone and coworkers (71) studied the effect of a low dose of acetazolamide on the neuromuscular control of breathing. Acetazolamide caused a 13% increase in minute ventilation and an 8% fall in PCO2. Acetazolamide caused a decrease in the responses of minute ventilation and tidal volume to increasing levels of hypercapnia, but it did not clearly alter the response of phrenic nerve output to hypercapnia. The authors conclude that acetazolamide causes a decrease in the ventilatory response to carbon dioxide, possibly through a direct effect on neuromuscular function. Widdicombe (72) recalls an early study on the neural pathways involved in cough. Pathophysiologic Studies in Volunteers
To determine the effect of endotoxin on control of breathing, Preas and coworkers (73) measured breathing pattern nonobtrusively in 12 healthy subjects who received endotoxin or placebo intravenously. Endotoxin produced an increase in body temperature of 2 C, an increase in respiratory frequency of 8 breaths per minute, and an increase in the alveolar to arterial oxygen gradient. These responses were blocked by the cyclooxygenase inhibitor, ibuprofen. Endotoxin produced increases in respiratory drive and dyspnea, which were not suppressed by ibuprofen. Endotoxin produced an increase in relationship between the value of respiratory frequency in a breath with the values of respiratory frequency in neighboring breaths. This relationship was related to the change in arterial PCO2 (r 0.86) and was blocked by ibuprofen. The authors conclude that endotoxemia causes increases in respiratory motor output and dyspnea independently of fever and symptoms, and it cur-
Year in Review
tails the freedom to vary respiratory timing—an effect that is mediated by the cyclooxygenase pathway. Guz (74) recalls an early study of the Hering-Breuer reflex in human subjects. Control of Breathing in Clinical Disorders
In a pulmonary perspective, Gozal and Gaultier (75) discuss evolving concepts on the maturation of central pathways involved in the ventilatory response to hypoxia. Dyspnea
To identify brain regions involved in dyspnea, Peiffer and coworkers (76) did positron emission tomography in eight healthy men breathing through an inspiratory and expiratory resistor. A high load increased the blood flow in three regions: the right anterior insula, the cerebellar vermis, and the medial pons. Blood flow in these three regions was correlated with the perceived intensity of discomfort and with swings in mouth pressure. In a fourth area, the right posterior cingulated cortex, neural activation was associated with the intensity of perceived discomfort but not with the swings in mouth pressure. The authors conclude that the discomfort during loaded breathing results from two processes: the first involved in perception of discomfort, and the second in modulating the perceived intensity, which may include emotional processing. An editorial commentary by Harper (77) accompanies this article.
RESPIRATORY MUSCLES Studies of Animals
High-frequency vibration of the rib cage decreases dyspnea, and causes increased inspiratory activity of the external intercostal muscles in dogs without altering tidal volume. Leduc and coworkers (78) asked whether concomitant contraction of the internal intercostal (expiratory) muscles might be responsible for keeping tidal volume constant. During apnea, vibration of the rib cage caused prominent activity in the external intercostals while the internal intercostals were silent. The internal intercostals were also silent when vibration was applied during spontaneous inspiration, and phasic expiratory activity did not change when vibration was applied during expiration. The authors conclude that the internal intercostal muscles do not interfere with the action of the external intercostals during vibration of the rib cage. To determine the role of the neuronal isoform of nitric oxide synthase in the diaphragmatic injury of sepsis, Comtois and coworkers (79) injected lipopolysaccharide into wild-type mice and knockout mice deficient in the gene for neuronal nitric oxide synthase. Lipopolysaccharide decreased maximum force of the diaphragm by about 25% in the wild-type mice and by about 40% in the knockout mice. Total activity of nitric oxide synthase increased in the wild-type mice due to the inducible nitric oxide synthase isoform. In the knockout mice, activity of nitric oxide synthase reached about 10% of that in the wildtype mice, and inducible nitric oxide synthase protein level reached about 60%. Stimulating isolated muscle strips for three minutes produces a sarcolemmal injury, and lipopolysaccharide increased this injury by about 50% in both the wild-type and knockout mice. The protein level of the endothelial isoform of nitric oxide synthase was not altered by lipopolysaccharide in either group of mice. The authors conclude that the neuronal isoform of nitric oxide synthase protects against the negative effect of endotoxin on diaphragmatic contractility, but it is not involved in the associated sarcolemmal injury. To determine the role of oxygen free radicals in causing diaphragmatic injury, Jiang and coworkers (80) had rabbits
591
breathe through an inspiratory resistor (airway pressure, 45 to 55 cm H2O) for 90 minutes. Three days later, the animals exposed to the load had a seven-fold increase in abnormal muscle and a 38% greater concentration of thiobarbituric acid reactive substances (TBARS, an index of free radical-mediated lipid peroxidation) in the diaphragm as compared with control animals. In vitro studies on strips from the diaphragm of the loaded animals revealed decreases in the twitch tension and maximal tension. When the animals were treated with free radical scavengers (polyethylene glycol superoxide dimutase, N-acetylcysteine, and mannitol) before the loading and 36 hours later, the fraction of abnormal muscle was 73% less than in the untreated animals, the concentration of TBARS was the same as in the unloaded animals, and diaphragmatic contractility was similar to that in the control group. The authors conclude that the production of oxygen free radicals is increased during the secondary phase of diaphragmatic injury, and that use of free radical scavengers can prevent the histological injury and partially preserve the in vitro characteristics of diaphragmatic contractility. The microsomal enzyme, heme oxygenase, catalyzes the oxidation of heme to biliverdin and carbon monoxide, providing a powerful protection against oxidative stress. Two isoforms have been identified: heme oxygenase 1, the inducible form (also known as heat shock protein 32), and heme oxygenase 2, the constitutive form. Taille and colleagues (81) determined whether this system protects against diaphragmatic dysfunction caused by endotoxin. Rats inoculated with endotoxin experienced a decrease in diaphragmatic contractility, and the diaphragmatic myocytes had enhanced expression of heme oxygenase 1. Expression was also enhanced in the rectus abdominis, the soleus muscle, and the left ventricle. Endotoxin did not modify the expression of heme oxygenase 2. Administration of an inhibitor of heme oxygenase activity, zinc protoporphyrin IX, further impaired the contractile failure and oxidative stress. Pretreatment with hemin, an inducer of heme oxygenase 1, completely prevented the oxidative stress and contractile failure. The authors conclude that the heme oxygenase pathway is a major cellular system for protecting the diaphragm against oxidative stress during sepsis. Dichloroacetate reduces the generation of lactic acid and increases the endurance of limb muscles. To determine whether dichloroacetate improves respiratory muscle performance, Ciufo and coworkers (82) exposed decerebrate rats to a large inspiratory resistive load (32,000 cm H2O per liter per second). Compared with unloaded rats, loaded rats had double the level of lactate in the diaphragm. Dichloroacetate prevented the increase in diaphragmatic lactate with loading. Compared with the control group, the rats treated with dichloroacetate tolerated loading poorly: they had a more rapid reduction in pressure generation by the diaphragm, and the time to respiratory arrest was shorter (42 versus 57 minutes). The authors conclude that dichloroacetate decreases the tolerance to inspiratory loading despite decreasing the concentration of lactate in the diaphragm. To investigate the effect of chronic hypoxemia on the discharge of afferent nerve fibers from skeletal muscle, Dousset and coworkers (83) exposed rats to a mixture of 10% oxygen in nitrogen for 45 days. Compared with normoxemic rats, the conduction velocity of groups I, II, and IV of muscle afferent fibers from the anterior tibial muscle was increased by 150 to 240% in the hypoxemic rats. Chronic hypoxemia depressed the response of the groups III and IV muscle afferents to injections of potassium chloride and abolished the response to lactic acid and electrically induced fatigue. The response of group I afferents to tendon vibrations (mechanoreceptors) was similar in the hypoxemic and normoxemic rats. The authors conclude that
592
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
chronic hypoxemia markedly alters the chemosensitivity of groups III and IV muscle afferents fibers, and that this finding may explain the greater vulnerability of hypoxemic subjects to fatigue. Infants with congenital diaphragmatic hernia have hypoplastic lungs and evidence of surfactant deficiency. To determine whether antenatal treatment with vitamin A would stimulate lung synthesis, Thebaud and coworkers (84) induced congenital diaphragmatic hernia in newborn rats by administering the herbicide, nitrofen, to pregnant rats on Day 12 of gestation. With this model, about 65% of exposed fetuses develop right-sided congenital diaphragmatic hernia. When delivered on Day 21, fetuses with congenital diaphragmatic hernia had reduced DNA content in their lungs, decreased surfactant disaturated phosphatidylcholine, decreased expression of surfactant protein-A and -C, and decreased type II cells. These abnormalities were reduced or returned to control values by treatment with vitamin A on Day 14. The authors conclude that antenatal treatment with vitamin A restores lung maturation in a rat model of congenital diaphragmatic hernia in terms of surfactant storage and expression. Rochester (85) recalls an early study of the blood flow to the diaphragm. Pathophysiologic Studies in Patients and Volunteers
Exercise. The antioxidant, reduced glutathione, inactivates reactive oxygen species by forming oxidized glutathione disulfide as the oxidation byproduct. The balance between reduced glutathione and oxidized glutathione can be used to assess the overall redox environment of the cell. In 17 patients with COPD (FEV1, 38% of predicted; PO2, 69 mm Hg), Rabinovich and coworkers (86) did needle biopsies of the vastus lateralis before and after endurance training (five days a week for eight weeks). Before training, the levels of reduced and oxidized glutathione were equivalent in the patients and the control subjects, both at rest and after 11 minutes of exercise. Training produced an 89% increase in reduced glutathione in healthy subjects but not in the patients. Training produced a 43% increase in oxidized glutathione in the patients but not in the control subjects. The increase in peak work rate induced by training was correlated with the rise in oxidized glutathione in the patients (r 0.55) and with the rise in reduced glutathione in the control subjects (r 0.83). Concentrations of messenger RNA for -glutamyl cysteine synthetase, a key enzyme in glutathione synthesis, tended to fall in the healthy subjects and to rise in the patients. The authors conclude that exercise training induces an increase in the antioxidant, reduced glutathione, in the limb muscle of healthy subjects but not in the muscles of patients with COPD, and that training produces an increase of oxidized glutathione in the muscles of patients but not in the muscles of healthy subjects. An editorial commentary by Reid (87) accompanies this article. Reference values of physiologic variables in response to exercise based on age and sex of a random population have not been published. Neder and coworkers (88) studied 60 men and 60 women, ranging in age from 20 to 80 years, who were randomly selected from 8,000 ancillary staff of a university. The subjects underwent a ramp incremental cardiopulmonary exercise test on a cycle ergometer, and the simultaneous rates of change in oxygen uptake, heart rate, ventilation, and tidal volume in relationship to work rate, carbon dioxide production, and oxygen consumptions were measured. Age, sex, and anthropometric attributes had influences on several of the dynamic relationships. A comprehensive set of linear prediction equations were developed, and the limits of normalcy (at the 95% confidence level) differed substantially from previous recommendations based on
VOL 165
2002
single discrete values. The authors conclude that the normative data provide a frame of reference for the normalcy of the submaximal responses of ventilatory, cardiovascular, and metabolic functions during rapidly incremental cycle ergometry in men and women up to 80 years of age. To determine whether the respiratory muscles contribute to the dyspnea that patients with congestive heart failure develop during exercise, Hughes and coworkers (89) studied eight patients with mild-to-moderate congestive heart failure and nine healthy controls. Subjects walked on a treadmill until they developed severe dyspnea or a minute ventilation of 100 liters per minute. At the end of the exercise, slowing of the maximum relaxation rate on the esophageal pressure tracing was 22% in the patients and 3% in the controls. There was no difference in inspiratory muscle effort, tidal volume, respiratory frequency, or heart rate in the two groups. The authors conclude that exercise causes slowing of the maximum relaxation rate in patients with congestive heart failure, indicating severe loading of the inspiratory muscles. In a pulmonary perspective, Debigare and colleagues (90) discuss wasting of the peripheral muscles in patients with COPD. Contractility and fatigue. To determine whether patients with respiratory disease develop central inhibition of the diaphragm while exercising to exhaustion, Sinderby and coworkers (91) studied 10 patients with COPD (FEV1, 33% predicted). Incremental exercise to exhaustion caused an increase in minute ventilation from 12 to 31 liters per minute. Transdiaphragmatic pressure increased from 9 to 13 cm H2O during early exercise, but it did not change thereafter. Electrical activity of the diaphragm was 24% of maximum at rest, and it increased progressively to 81% of maximum at the end of exercise. Lung volume at the end of inspiration was 86% of total lung capacity at rest, and it was 97% of total lung capacity at the end of exercise. The authors conclude that transdiaphragmatic pressure increases only modestly during maximum exercise in patients with COPD, and that the minor nature of the increase is secondary to the development of dynamic hyperinflation rather than to inhibition of central drive. While breathing against a constant load, subjects develop an increase in the sense of respiratory effort over time. To investigate how the activation of the diaphragm and the generation of pressure influence this phenomenon, Sinderby and coworkers (92) studied six subjects while they performed two 10-minute periods of targeted breathing. Electrical activation of the diaphragm was increased to 40% of maximum by two strategies: generating a maximum transdiaphragmatic pressure of 55 cm H2O (by either expulsive or Mueller maneuvers) or by inspiring to 71% of inspiratory capacity (generating transdiaphragmatic pressure of 21 cm H2O). The sensation of respiratory effort increased over time with both forms of targeted breathing. The center frequency of the power spectrum of the diaphragmatic EMG decreased over time, and the decrease was greater when subjects were generating a greater transdiaphragmatic pressure. Plotting the change in the power spectrum against the sense of effort produced identical slopes for the two forms of targeted breathing. The authors conclude that while generating a constant level of diaphragmatic activation, subjects develop an increased sense of effort over time and that the increased effort is associated with proportional change in the center frequency of the power spectrum, and is independent of transdiaphragmatic pressure. Diagnostic Studies
To determine the effect of maturation on diaphragmatic function, Dimitriou and coworkers (93) studied 28 infants with a post-conceptional age of 37.6 weeks (range, 25 to 44 weeks).
593
Year in Review
Transdiaphragmatic pressure during crying was 16% lower in 12 infants who were preterm (post-conceptional age of 37 weeks or lower); the pressure was correlated with post-conceptional age (r 0.44). In 14 infants, transdiaphragmatic pressure during crying was correlated with maximum inspiratory pressure (r 0.79). The authors conclude that maturation affects diaphragmatic function. Structure and Histology
To determine whether patients with airflow obstruction experience injury to their diaphragm, MacGowan and coworkers (94) did partial thickness biopsies of the diaphragm in 21 patients undergoing thoracotomy. The FEV1 of the patients ranged from 16 to 122% of predicted, mean 74%. The contributions to the cross-sectional area were: normal diaphragm, 66%; abnormal muscle, 18%; and connective tissue, 16%. The abnormal tissue included fibers with internally located nuclei, lipofuscin pigmentation, small angulated fibers, and some inflammation. The percent predicted FEV1 was inversely related to the area of abnormal muscle (r 0.53), but not to the number of macrophages present. The authors conclude that patients with increasing severity of airway obstruction have a proportional increase in abnormal tissue in their diaphragm. To determine whether the diaphragm of patients with COPD displays ultrastructural evidence of injury and whether acute loading induces diaphragmatic injury, Orozco-Levi and coworkers (95) obtained biopsies from the costal diaphragm in 18 patients with COPD and in 11 healthy subjects during surgery. Electron microscopy revealed sarcomere disruptions in all of the samples, and the density and area of disruptions in the patients were twice that seen in control subjects. The density of sarcomere disruptions was correlated with FEV1 (r 0.59) and with the ratio of residual volume to total lung capacity (r 0.80). Before the surgery, a subset of seven patients with COPD and five control subjects breathed through a threshold resistor until task failure. Compared with the unloaded state, the density of sarcomere disruptions increased by 89% in the loaded healthy subjects and by 38% in the loaded patients. The density of disruptions was about three times greater in the patients with COPD after loading as compared with the unloaded healthy subjects. The authors conclude that sarcomere disruptions are increased in the diaphragm of patients with COPD, and that acute loading causes sarcomere disruption in the diaphragm of both healthy subjects and patients with COPD. Respiratory Muscle Involvement in Clinical Disorders
Studies of respiratory function in patients with Duchenne muscular dystrophy have mostly been cross-sectional rather than longitudinal in nature. Phillips and coworkers (96) analyzed data on 58 patients who had repeated measurements of spirometry over at least 2 years. At entry, median forced vital capacity (FVC) was 1.65 liter (range, 0.45 to 2.75 liter) or 64% of predicted (range, 29 to 97%). The rate of change in FVC varied, with a median annual change of 0.18 liter (range 0.04 to 0.74 liter) or of 8% of predicted (range, 2 to 39%). During the study, 37 patients died and the median age at death was 22 years (range, 15 to 29 years). The age at which FVC fell below 1 liter was a strong predictor of mortality: only 8% lived for another 5 years after reaching that value. The authors conclude that repeated spirometry provides a powerful means of assessing disease progression in patients with Duchenne muscular dystrophy, and that the age at which FVC falls below 1 liter is an appropriate point at which to consider more intensive management.
PULMONARY FUNCTION TESTING Equipment and Techniques
To determine whether the absence of teeth influences spirometry, Bucca and coworkers (97) measured spirometry in 36 healthy subjects, 22 patients with COPD, and 18 patients with interstitial lung disease. Removing dentures caused the peak expiratory flow rate (PEFR) to fall by 17% in the healthy subjects and by 7% in the patients with interstitial lung disease. Removing dentures had no effect in the patients with COPD. Removing dentures had no effect on FEV1 or FVC in any group. Removing dentures caused the retropharyngeal space to decrease by 24%. The authors conclude that removing dentures results in a smaller peak flow rate in healthy subjects and in patients with interstitial lung disease. The induction of sputum is thought to selectively sample the central airways, but direct support for the claim does not exist. Alexis and coworkers (98) addressed this issue in 10 healthy subjects using a novel system for generating and delivering an aerosol. To maximize deposition in the central airways, the subjects inhaled radiolabeled (99mTc) sulfur colloid particles within large droplets (6 m) with a tidal volume of 500 ml. To maximize deposition in the peripheral airways, the subjects inhaled radiolabeled particles in 0.7-m droplets with a tidal volume of 1,000 ml. Use of maneuvers to increase central deposition of aerosol resulted in 16.6 times more radioactivity in induced sputum, as compared with maneuvers to increase peripheral deposition of aerosol. Clearance from the whole lung was 9.6 times greater at 40 minutes after central deposition as compared with after peripheral deposition. Compared with control, the induction of sputum achieved a 4.4-fold increase in clearance after central deposition, but no increase in clearance after peripheral deposition. The authors conclude that the induction of sputum samples the central airways, and that it derives little or no contribution from the peripheral airways. Bates (99) recalls the use of xenon in an early study of regional lung function. Weibel (100) recalls an early study of the structure of the lung. Tenney (101) recalls a study on estimating the surface area of the lung. Epidemiology Studies
Because the correlation in decline in FEV1 among family members has not been reported, Kurzius-Spencer and coworkers (102) analyzed data on 392 families enrolled in the Tucson Epidemiological Study. The subjects were older than 18 years and had at least three measurements of pulmonary function over 5 to 20 years. The slope of FEV1 was not correlated between parents and offspring. The slope of FEV1 was correlated between sibling pairs (r 0.26), especially for smoking-concordant pairs (r 0.48 for ever-smokers and r 0.28 for never-smokers). Smoking-discordant siblings did not show a correlation (r 0.03). The authors conclude that the high correlation between siblings for decline in FEV1 and the lack of correlation between parents and offspring is compatible with a recessive model of inheritance. Because the heritability of the longitudinal change in lung function has not been previously investigated, Gottlieb and coworkers (103) analyzed data collected over several decades in two generations of families participating in the Framingham Heart Study. Spirometry in the original cohort was performed in 1960–1961 and 1974–1975, and in the offspring cohort in 1984–1987 and 1992–1995. After adjusting for age, body habitus, and smoking status on multiple linear regression analyses, heritable factors accounted for a modest proportion of the
594
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
change in spirometry: the estimated heritability was 0.05 for the standardized residual of FEV1, 0.18 for FVC, and 0.13 for FEV1/FVC ratio. Among subjects concordant for smoking status, the heritability estimates were 0.18 for FEV1, 0.39 for FVC, and 0.14 for FEV1/FVC ratio. The authors conclude that genetic factors contribute modestly to the rate of change in lung function, and that gene–environment interactions contribute to this variance. Use of estrogen and progesterone has been associated with improved pulmonary function in premenopausal women. To determine the relationship between hormone replacement therapy and pulmonary function in postmenopausal women, Carlson and coworkers (104) analyzed data from 2,353 women aged 65 years and older participating in the Cardiovascular Health Study. Current users of hormone therapy had a 9.6% higher FEV1 as compared with nonusers. Higher levels of FEV1 were found in several subgroups: women without asthma (9.4%), former smokers (10%), and never-smokers (10%). After controlling for confounding variables, hormone therapy was associated with a higher FEV1 and a lower prevalence of airway obstruction (odds ratio, 0.67). The authors conclude that hormone replacement therapy in postmenopausal women is associated with improved lung function and less airway obstruction. Because airway obstruction is thought to result from an imbalance between oxidants and antioxidants, and because vitamin C, vitamin E, retinol, and carotenoids are powerful antioxidants, Schunemann and coworkers (105) examined the relationship between serum levels of these antioxidants and lung function in a cross-sectional study of 1,616 healthy individuals, aged 35 to 79 years. Subjects in the lowest quartile for each of the serum antioxidants had lower FEV1 and FVC values as compared with the subjects in the higher quartiles. In a multivariate regression model, vitamin E and -cryptoxanthin had the strongest association with FEV1. The differences in FEV1, associated with the reduction of one standard deviation of serum vitamin E or -cryptoxanthin, were equivalent to the negative influence of about 1 to 2 years of aging. The authors conclude that antioxidant vitamins have an important influence on lung function. African Americans have lower lung function than whites. To assess the contribution of body habitus and socioeconomic factors to the difference, Harik-Khan and coworkers (106) analyzed data from 1,242 white and 1,084 African-American asymptomatic, nonsmokers in the third National Health and Nutrition Examination Survey (NHANES III). Compared with whites, African Americans were poorer, had a lower sitting height, a lower FEV1 and FVC, a larger FEV1/FVC ratio, and a greater body mass index. On cross-sectional regression analyses, the sitting height accounted for 35–39% of the race difference in spirometry, the poverty index for 7.5% of the race difference in the women and 2.5% of the race difference in the men, and education for 2% of the race difference in the women and 4.7% in the men. With further adjustment for body mass index, only about half of the racial difference in FEV1 and FVC could be accounted for. The authors conclude that a shorter upper body segment and lower socioeconomic status only partially explains the lower lung function in African Americans. To determine predictors of loss of lung function in the elderly, Griffith and coworkers (107) analyzed data on 5,242 subjects enrolled in the Cardiovascular Health Study. Subjects had a mean age of 73 years, 58% were women, and 88% were white. African Americans had lower spirometry levels, but the rate of decline in FEV1 with age was less. Spirometry levels were lower in patients with chronic bronchitis, pneumonia, asthma, and emphysema, and in subjects reporting systolic
VOL 165
2002
blood pressure above 160 mm Hg, use of -blockers, or congestive heart failure. Past smoking was associated with lower FEV1, but only current smokers experienced a greater annual decline. Patients with asthma had a 500 ml lower FEV1 at baseline, but they did not experience an accelerated decline. The authors conclude that current smokers, especially men, experience a more rapid rate of decline in FEV1. An association between impaired pulmonary function and cardiovascular mortality has been reported, but the mechanism is not clear. To determine whether stiffness of the aorta is associated with impaired pulmonary function, Zureik and coworkers (108) did a cross-sectional study in 194 men who were free of coronary heart disease. The velocity of the pulse wave between the carotid and femoral artery, which is proportional to aortic stiffness, was negatively associated with FEV1 (r 0.27) and FVC (r 0.24). For every 1 standard deviation increase in pulse-wave velocity, FEV1 decreased by 195 ml. Adjustments for other cardiovascular risk factors (weight, smoking, hypertension) did not substantially alter the findings. The authors conclude that an increase in the stiffness of the aorta is independently associated with a decrease in lung function. In Acromegaly
Patients with acromegaly have increased lung volume, but it is unclear whether it results from alveolar hypertrophy or alveolar hyperplasia. To investigate this issue, Garcia-Rio and coworkers (109) studied 11 patients with acromegaly and 11 matched control subjects. Total lung capacity was 23% higher, specific lung compliance 21% higher, the shape constant of the pressure–volume curve 83% higher, and maximal recoil pressure 25% lower in patients with acromegaly as compared with the control subjects; diffusing capacity did not differ between the two groups. Suppressing the hypersecretion of growth hormone with surgery or with analogs of somatostatin produced a 9% decrease in total lung capacity, a 24% decrease in specific lung compliance, a 48% decrease in the shape constant of the pressure–volume curve, and a 31% increase in maximal recoil pressure. The authors conclude that the increase in lung volume in patients with acromegaly is secondary to an increase in alveolar size. In Mitochondrial Myopathy
Of 331 patients with unexplained dyspnea on exertion, Flaherty and coworkers (110) found 28 patients (8.5%) had a mitochondrial myopathy on biopsy. Compared with control subjects, the patients had a 31% lower maximum inspiratory pressure and a 26% lower maximum oxygen consumption during exercise. During exercise, the patients had a 31% higher ventilatory response to carbon dioxide, and a 2.2 times higher heart rate, when normalized to maximum oxygen consumption, as compared with the control subjects. Sixteen patients (57%) stopped exercise because of dyspnea; these patients had a 47% decrease in maximum transdiaphragmatic pressure and were more likely to reach their mechanical ventilatory limitation. The patients had normal spirometry, lung volumes, and gas exchange. The authors conclude that mitochondrial myopathies are more prevalent than commonly suspected, and that affected patients demonstrate a characteristic hyperventilatory and hypercirculatory response on exercise testing. Bronchoscopy
The AccuTouch bronchoscopy simulator includes a robotic interface and simulation software. Ost and coworkers (111) evaluated the simulator in two ways: to determine whether it could discriminate between experienced and nonexperienced
Year in Review
bronchoscopists; and to determine whether it could contribute to the training of new fellows. The procedure was completed by nine experts (who had done more than 500 bronchoscopies) in 55% less time than it took 11 novices (residents or nurses who had never done a bronchoscopy) and in 17% less time than it took 8 fellows (who had done 25 to 500 bronchoscopies). The experts experienced 53% fewer bronchoscopic collisions than did the novices and 17% fewer than did the fellows. Compared with fellows trained by conventional means, fellows trained with the simulator took 18% less time to do their first bronchoscopy, and the ratio of segments correctly identified per procedure time was 2.5-fold higher. The authors conclude that the bronchoscopy simulator can be used to test a physician’s experience in doing bronchoscopies, and that it can assist in the training of fellows. References 1. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier NF, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25. 2. Hedner J, Grote L. The link between sleep apnea and cardiovascular disease: time to target the nonsleepy sleep apneics? Am J Respir Crit Care Med 2001;163:5–6. 3. Guidry UC, Mendes LA, Evans JC, Levy D, O’Connor GT, Larson MG, Gottlieb DJ, Benjamin EJ. Echocardiographic features of the right heart in sleep-disordered breathing: the Framingham Heart Study. Am J Respir Crit Care Med 2001;164:933–938. 4. Fishman AP. On keeping an eye on the right ventricle in sleep apnea. Am J Respir Crit Care Med 2001;164:913–914. 5. Niroumand M, Kuperstein R, Sasson Z, Hanly PJ. Impact of obstructive sleep apnea on left ventricular mass and diastolic function. Am J Respir Crit Care Med 2001;163:1632–1636. 6. Duran J, Esnaola S, Rubio R, Iztueta A. Obstructive sleep apnea-hypopnea and related clinical features in a population-based sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med 2001;163:685–689. 7. Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163:608–613. 8. Menopause YT. hormone replacement therapy, and sleep-disordered breathing: are we ready for the heat? Am J Respir Crit Care Med 2001;163:597–598. 9. Lindberg E, Carter N, Gislason T, Janson C. Role of snoring and daytime sleepiness in occupational accidents. Am J Respir Crit Care Med 2001;164:2031–2035. 10. Carmelli D, Bliwise DL, Swan GE, Reed T. Genetic factors in selfreported snoring and excessive daytime sleepiness: a twin study. Am J Respir Crit Care Med 2001;164:949–952. 11. Mooe T, Franklin KA, Holmstrom K, Rabben T, Wiklund U. Sleepdisordered breathing and coronary artery disease. Long-term prognosis. Am J Respir Crit Care Med 2001;164:1910–1913. 12. Cakirer B, Hans MG, Graham G, Aylor J, Tishler PV, Redline S. The relationship between craniofacial morphology and obstructive sleep apnea in whites and in African-Americans. Am J Respir Crit Care Med 2001;163:947–950. 13. Polotsky VY, Wilson JA, Smaldone MC, Haines AS, Hurn PD, Tankersley CG, Smith PL, Schwartz AR, O’Donnell CP. Female gender exacerbates respiratory depression in leptin-deficient obesity. Am J Respir Crit Care Med 2001;164:1470–1475. 14. Khoo MC, Belozeroff V, Berry RB, Sassoon CS. Cardiac Autonomic Control in Obstructive Sleep Apnea: effects of long-term cpap therapy. Am J Respir Crit Care Med 2001;164:807–812. 15. Leung RS, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med 2001;164:2147–2165. 16. Elliott AR, Shea SA, Dijk DJ, Wyatt JK, Riel E, Neri DF, Czeisler CA, West JB, Prisk GK. Microgravity reduces sleep-disordered breathing in humans. Am J Respir Crit Care Med 2001;164:478–485. 17. Dinges DF. Sleep in space flight: breath easy–sleep less? Am J Respir Crit Care Med 2001;164:337–338. 18. Fogel RB, Malhotra A, Pillar G, Edwards JK, Beauregard J, Shea SA, White DP. Genioglossal activation in patients with obstructive sleep apnea versus control subjects: mechanisms of muscle control. Am J Respir Crit Care Med 2001;164:2025–2030.
595 19. Remmers JE. Wagging the tongue and guarding the airway: reflex control of the genioglossus. Am J Respir Crit Care Med 2001;164:2013– 2014. 20. Kimoff RJ, Sforza E, Champagne V, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:250–255. 21. Svanborg E. Upper airway nerve lesions in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:187–189. 22. Arens R, McDonough JM, Costarino AT, Mahboubi S, Tayag-Kier CE, Maislin G, Schwab RJ, Pack AI. Magnetic resonance imaging of the upper airway structure of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2001;164:698–703. 23. Kuna ST. Effects of pharyngeal muscle activation on airway size and configuration. Am J Respir Crit Care Med 2001;164:1236–1241. 24. Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2001;163:1181–1190. 25. Khoo MC. Using loop gain to assess ventilatory control in obstructive sleep apnea. Am J Respir Crit Care Med 2001;163:1044–1045. 26. Dempsey JA, Skatrud JB. Apnea following mechanical ventilation may be caused by nonchemical neuromechanical influences. Am J Respir Crit Care Med 2001;163:1297–1298. 27. Younes M. Apnea following mechanical ventilation may not be caused by neuromechanical influences. Am J Respir Crit Care Med 2001;163: 1298–1301. 28. Dempsey JA, Skatrud JB. Rebuttal. Am J Respir Crit Care Med 2001; 163:1300. 29. Younes M. Rebuttal. Am J Respir Crit Care Med 2001;163:1300–1301. 30. Guilleminault C, Faul JL, Stoohs R. Sleep-disordered breathing and hypotension. Am J Respir Crit Care Med 2001;164:1242–1247. 31. Freedman NS, Gazendam J, Levan L, Pack AI, Schwab RJ. Abnormal sleep/wake cycles and the effect of environmental noise on sleep disruption in the intensive care unit. Am J Respir Crit Care Med 2001; 163:451–457. 32. Uong EC, McDonough JM, Tayag-Kier CE, Zhao H, Haselgrove J, Mahboubi S, Schwab RJ, Pack AI, Arens R. Magnetic resonance imaging of the upper airway in children with Down syndrome. Am J Respir Crit Care Med 2001;163:731–736. 33. Kato I, Groswasser J, Franco P, Scaillet S, Kelmanson I, Togari H, Kahn A. Developmental characteristics of apnea in infants who succumb to sudden infant death syndrome. Am J Respir Crit Care Med 2001;164:1464–1469. 34. Hunt CE. Sudden infant death syndrome and other causes of infant mortality: diagnosis, mechanisms, and risk for recurrence in siblings. Am J Respir Crit Care Med 2001;164:346–357. 35. Marcus CL. Sleep-disordered breathing in children. Am J Respir Crit Care Med 2001;164:16–30. 36. Adams N, Strauss M, Schluchter M, Redline S. Relation of measures of sleep-disordered breathing to neuropsychological functioning. Am J Respir Crit Care Med 2001;163:1626–1631. 37. Farre R, Rigau J, Montserrat JM, Ballester E, Navajas D. Relevance of linearizing nasal prongs for assessing hypopneas and flow limitation during sleep. Am J Respir Crit Care Med 2001;163:494–497. 38. Thurnheer R, Xie X, Bloch KE. Accuracy of nasal cannula pressure recordings for assessment of ventilation during sleep. Am J Respir Crit Care Med 2001;164:1914–1919. 39. Cracowski C, Pepin JL, Wuyam B, Levy P. Characterization of obstructive nonapneic respiratory events in moderate sleep apnea syndrome. Am J Respir Crit Care Med 2001;164:944–948. 40. Gurubhagavatula I, Maislin G, Pack AI. An algorithm to stratify sleep apnea risk in a sleep disorders clinic population. Am J Respir Crit Care Med 2001;164:1904–1909. 41. Hosselet J, Ayappa I, Norman RG, Krieger AC, Rapoport DM. Classification of sleep-disordered breathing. Am J Respir Crit Care Med 2001;163:398–405. 42. Priest B, Brichard C, Aubert G, Liistro G, Rodenstein DO. Microsleep during a simplified maintenance of wakefulness test: a validation study of the OSLER test. Am J Respir Crit Care Med 2001;163:1619–1625. 43. Bliwise DL. Is the measurement of sleepiness the Holy Grail of sleep medicine? Am J Respir Crit Care Med 2001;163:1517–1519. 44. Chervin RD. Periodic leg movements and sleepiness in patients evaluated for sleep-disordered breathing. Am J Respir Crit Care Med 2001;164:1454–1458. 45. Walters AS. Assessment of periodic leg movements is an essential component of an overnight sleep study. Am J Respir Crit Care Med 2001; 164:1339–1340. 46. Mahowald MW. Assessment of periodic leg movements is not an essen-
596
47. 48. 49. 50.
51.
52.
53.
54.
55.
56.
57. 58.
59.
60.
61.
62.
63.
64.
65. 66.
67. 68.
69.
70.
71.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE tial component of an overnight sleep study. Am J Respir Crit Care Med 2001;164:1340–1341. Walters AS. Rebuttal. Am J Respir Crit Care Med 2001;164:1341–1342. Mahowald MW. Rebuttal. Am J Respir Crit Care Med 2001;164:1342. Douglas NJ. “Why am I sleepy?”: sorting the somnolent. Am J Respir Crit Care Med 2001;163:1310–1313. Montserrat JM, Ferrer M, Hernandez L, Farre R, Vilagut G, Navajas D, Badia JR, Carrasco E, De Pablo J, Ballester E. Effectiveness of CPAP treatment in daytime function in sleep apnea syndrome: a randomized controlled study with an optimized placebo. Am J Respir Crit Care Med 2001;164:608–613. Monasterio C, Vidal S, Duran J, Ferrer M, Carmona C, Barbe F, Mayos M, Gonzalez-Mangado N, Juncadella M, Navarro A, et al. Effectiveness of continuous positive airway pressure in mild sleep apneahypopnea syndrome. Am J Respir Crit Care Med 2001;164:939–943. McArdle N, Douglas NJ. Effect of continuous positive airway pressure on sleep architecture in the sleep apnea-hypopnea syndrome: a randomized controlled trial. Am J Respir Crit Care Med 2001;164:1459–1463. Faccenda JF, Mackay TW, Boon NA, Douglas NJ. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001;163:344–348. Karlawish JH, Pack AI. Addressing the ethical problems of randomized and placebo-controlled trials of CPAP. Am J Respir Crit Care Med 2001;163:809–810. Henke KG, Grady JJ, Kuna ST. Effect of nasal continuous positive airway pressure on neuropsychological function in sleep apnea-hypopnea syndrome: a randomized, placebo-controlled trial. Am J Respir Crit Care Med 2001;163:911–917. Randerath WJ, Schraeder O, Galetke W, Feldmeyer F, Ruhle KH. Autoadjusting CPAP therapy based on impedance efficacy, compliance and acceptance. Am J Respir Crit Care Med 2001;163:652–657. Levy P, Pepin JL. Autoadjusting continuous positive airway pressure: what can we expect? Am J Respir Crit Care Med 2001;163:1295–1296. Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001;164:614–619. Milross MA, Piper AJ, Norman M, Becker HF, Willson GN, Grunstein RR, Sullivan CE, Bye PT. Low-flow oxygen and bilevel ventilatory support: effects on ventilation during sleep in cystic fibrosis. Am J Respir Crit Care Med 2001;163:129–134. Pack AI, Black JE, Schwartz JR, Matheson JK. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:1675–1681. Kingshott RN, Vennelle M, Coleman EL, Engleman HM, Mackay TW, Douglas NJ. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 2001;163:918–923. Mehta A, Qian J, Petocz P, Darendeliler MA, Cistulli PA. A randomized, controlled study of a mandibular advancement splint for obstructive sleep apnea. Am J Respir Crit Care Med 2001;163:1457–1461. Ferguson K. Oral appliance therapy for obstructive sleep apnea: finally evidence you can sink your teeth into. Am J Respir Crit Care Med 2001;163:1294–1295. Fritsch KM, Iseli A, Russi EW, Bloch KE. Side effects of mandibular advancement devices for sleep apnea treatment. Am J Respir Crit Care Med 2001;164:813–818. Pack AI. Rip Van Winkle: will academic pulmonary programs ever wake up to sleep? Am J Respir Crit Care Med 2001;164:2143–2144. Nakano H, Magalang UJ, Lee SD, Krasney JA, Farkas GA. Serotonergic modulation of ventilation and upper airway stability in obese Zucker rats. Am J Respir Crit Care Med 2001;163:1191–1197. Veasey SC. Serotonin: culprit or promising therapy for obstructive sleep apnea? Am J Respir Crit Care Med 2001;163:1045–1047. Nakano H, Lee SD, Ray AD, Krasney JA, Farkas GA. Role of nitric oxide in thermoregulation and hypoxic ventilatory response in obese Zucker rats. Am J Respir Crit Care Med 2001;164:437–442. Polotsky VY, Wilson JA, Haines AS, Scharf MT, Soutiere SE, Tankersley CG, Smith PL, Schwartz AR, O’Donnell CP. The impact of insulin-dependent diabetes on ventilatory control in the mouse. Am J Respir Crit Care Med 2001;163:624–632. Kiwull-Schone H, Wiemann M, Frede S, Bingmann D, Wirth KJ, Heinelt U, Lang HJ, Kiwull P. A novel inhibitor of the Na /H exchanger type 3 activates the central respiratory CO2 response and lowers the apneic threshold. Am J Respir Crit Care Med 2001;164: 1303–1311. Kiwull-Schone HF, Teppema LJ, Kiwull PJ. Low-dose acetazolamide
72. 73.
74.
75.
76.
77. 78.
79.
80.
81.
82.
83.
84.
85.
86.
87. 88.
89.
90.
91.
92.
93.
94.
95.
VOL 165
2002
does affect respiratory muscle function in spontaneously breathing anesthetized rabbits. Am J Respir Crit Care Med 2001;163:478–483. Widdicombe J. The race to explore the pathway to cough: who won the silver medal? Am J Respir Crit Care Med 2001;164:729–730. Preas HL, Jubran A, Vandivier RW, Reda D, Godin PJ, Banks SM, Tobin MJ, Suffredini AF. Effect of endotoxin on ventilation and breath variability: role of cyclooxygenase pathway. Am J Respir Crit Care Med 2001;164:620–626. Guz A. Hering and Breuer revisited in humans: an invasive study before the days of ethics committees. Am J Respir Crit Care Med 2001; 164:1110–1111. Gozal D, Gaultier C. Evolving concepts of the maturation of central pathways underlying the hypoxic ventilatory response. Am J Respir Crit Care Med 2001;164:325–329. Peiffer C, Poline JB, Thivard L, Aubier M, Samson Y. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 2001;163:951–957. Harper RM. Visualization of neural activity associated with dyspnea. Am J Respir Crit Care Med 2001;163:805–806. Leduc D, Brunko E, De Troyer A. Response of the canine internal intercostal muscles to chest wall vibration. Am J Respir Crit Care Med 2001;163:49–54. Comtois AS, Barreiro E, Huang PL, Marette A, Perrault M, Hussain SN. Lipopolysaccharide-induced diaphragmatic contractile dysfunction and sarcolemmal injury in mice lacking the neuronal nitric oxide synthase. Am J Respir Crit Care Med 2001;163:977–982. Jiang TX, Reid WD, Road JD. Free radical scavengers and diaphragm injury following inspiratory resistive loading. Am J Respir Crit Care Med 2001;164:1288–1294. Taille C, Foresti R, Lanone S, Zedda C, Green C, Aubier M, Motterlini R, Boczkowski J. Protective role of heme oxygenases against endotoxin-induced diaphragmatic dysfunction in rats. Am J Respir Crit Care Med 2001;163:753–761. Ciufo R, Dimarco A, Stofan D, Nethery D, Supinski G. Dichloroacetate reduces diaphragmatic lactate formation but impairs respiratory performance. Am J Respir Crit Care Med 2001;164:1669–1674. Dousset E, Decherchi P, Grelot L, Jammes Y. Effects of chronic hypoxemia on the afferent nerve activities from skeletal muscle. Am J Respir Crit Care Med 2001;164:1476–1480. Thebaud B, Barlier-Mur AM, Chailley-Heu B, Henrion-Caude A, Tibboel D, Dinh-Xuan AT, Bourbon JR. Restoring effects of vitamin A on surfactant synthesis in nitrofen-induced congenital diaphragmatic hernia in rats. Am J Respir Crit Care Med 2001;164:1083–1089. Rochester DF. Energy expenditure of the diaphragm or “he thinks the diaphragm is the heart”. Am J Respir Crit Care Med 2001;164:2145– 2146. Rabinovich RA, Ardite E, Troosters T, Carbo N, Alonso J, Gonzalez de Suso JM, Vilaro J, Barbera JA, Polo MF, Argiles JM, et al. Reduced muscle redox capacity after endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1114–1118. Reid MB. COPD as a muscle disease. Am J Respir Crit Care Med 2001;164:1101–1102. Neder JA, Nery LE, Peres C, Whipp BJ. Reference values for dynamic responses to incremental cycle ergometry in males and females aged 20 to 80. Am J Respir Crit Care Med 2001;164:1481–1486. Hughes PD, Hart N, Hamnegard CH, Green M, Coats AJ, Moxham J, Polkey MI. Inspiratory muscle relaxation rate slows during exhaustive treadmill walking in patients with chronic heart failure. Am J Respir Crit Care Med 2001;163:1400–1403. Debigare R, Cote CH, Maltais F. Peripheral muscle wasting in chronic obstructive pulmonary disease. Clinical relevance and mechanisms. Am J Respir Crit Care Med 2001;164:1712–1717. Sinderby C, Spahija J, Beck J, Kaminski D, Yan S, Comtois N, Sliwinski P. Diaphragm activation during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1637–1641. Sinderby C, Spahija J, Beck J. Changes in respiratory effort sensation over time are linked to the frequency content of diaphragm electrical activity. Am J Respir Crit Care Med 2001;163:905–910. Dimitriou G, Greenough A, Rafferty GF, Moxham J. Effect of maturity on maximal transdiaphragmatic pressure in infants during crying. Am J Respir Crit Care Med 2001;164:433–436. Macgowan NA, Evans KG, Road JD, Reid WD. Diaphragm injury in individuals with airflow obstruction. Am J Respir Crit Care Med 2001; 163:1654–1659. Orozco-Levi M, Lloreta J, Minguella J, Serrano S, Broquetas JM, Gea J. Injury of the human diaphragm associated with exertion and chronic
597
Year in Review
96.
97.
98.
99. 100. 101. 102.
103.
104.
obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164: 1734–1739. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with duchenne muscular dystrophy. Am J Respir Crit Care Med 2001;164:2191– 2194. Bucca CB, Carossa S, Colagrande P, Brussino L, Chiavassa G, Pera P, Rolla G, Preti G. Effect of edentulism on spirometric tests. Am J Respir Crit Care Med 2001;163:1018–1020. Alexis NE, Hu SC, Zeman K, Alter T, Bennett WD. Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery technique. Am J Respir Crit Care Med 2001; 164:1964–1970. Bates DV. Enter the stranger: the story of xenon. Am J Respir Crit Care Med 2001;163:1302–1303. Weibel ER. Why measure lung structure? Am J Respir Crit Care Med 2001;163:314–315. Tenney SM. On the merit of making comparisons. Am J Respir Crit Care Med 2001;164:5–6. Kurzius-Spencer M, Sherrill DL, Holberg CJ, Martinez FD, Lebowitz MD. Familial correlation in the decline of forced expiratory volume in one second. Am J Respir Crit Care Med 2001;164:1261–1265. Gottlieb DJ, Wilk JB, Harmon M, Evans JC, Joost O, Levy D, O’Connor GT, Myers RH. Heritability of longitudinal change in lung function: The Framingham study. Am J Respir Crit Care Med 2001;164: 1655–1659. Carlson CL, Cushman M, Enright PL, Cauley JA, Newman AB. Hor-
105.
106.
107.
108.
109.
110.
111.
mone replacement therapy is associated with higher FEV1 in elderly women. Am J Respir Crit Care Med 2001;163:423–428. Schunemann HJ, Grant BJ, Freudenheim JL, Muti P, Browne RW, Drake JA, Klocke RA, Trevisan M. The relation of serum levels of antioxidant vitamins C and E, retinol and carotenoids with pulmonary function in the general population. Am J Respir Crit Care Med 2001;163:1246–1255. Harik-Khan RI, Fleg JL, Muller DC, Wise RA. The effect of anthropometric and socioeconomic factors on the racial difference in lung function. Am J Respir Crit Care Med 2001;164:1647–1654. Griffith KA, Sherrill DL, Siegel EM, Manolio TA, Bonekat HW, Enright PL. Predictors of loss of lung function in the elderly: the Cardiovascular Health Study. Am J Respir Crit Care Med 2001;163:61–68. Zureik M, Benetos A, Neukirch C, Courbon D, Bean K, Thomas F, Ducimetiere P. Reduced pulmonary function is associated with central arterial stiffness in men. Am J Respir Crit Care Med 2001;164:2181–2185. Garcia-Rio F, Pino JM, Diez JJ, Ruiz A, Villasante C, Villamor J. Reduction of lung distensibility in acromegaly after suppression of growth hormone hypersecretion. Am J Respir Crit Care Med 2001; 164:852–857. Flaherty KR, Wald J, Weisman IM, Zeballos RJ, Schork MA, Blaivas M, Rubenfire M, Martinez FJ. Unexplained exertional limitation: characterization of patients with a mitochondrial myopathy. Am J Respir Crit Care Med 2001;164:425–432. Ost D, De Rosiers A, Britt EJ, Fein AM, Lesser ML, Mehta AC. Assessment of a bronchoscopy simulator. Am J Respir Crit Care Med 2001;164:2248–2255.
