Sleep-Disordered Breathing, Control of Breathing ... - ATS Journals

Year in Review Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, Pulmonary Function Testing in AJRCCM 2003 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 (41) Epidemiology (5) Risk Factors (1) Pathophysiology (17) Cardiovascular Mechanisms (4) Upper Airway Mechanisms (7) Control of Breathing (6) Clinical Aspects (5) In Critically Ill Patients (1) In Children (4) Diagnostic Techniques (1) Treatment (12) Airway Pressure and Flow (5) Pharmacotherapy (4) Mandibular Devices (1) Surgery (1) Obesity Management (1) Control of Breathing (8) Studies in Animals (3) Pathophysiological Studies in Volunteers (3) Control of Breathing in Clinical Disorders (2) Respiratory Muscles (18) Studies in Animals (1) Mechanical Ventilation (1) Pathophysiological Studies in Patients and Volunteers (17) Exercise and Peripheral Muscles (8) Chest Wall Motion (2) Diagnostic Studies (1) Respiratory Muscle Involvement in Clinical Disorders (6) Pulmonary Function Testing and Bronchoscopy (14) Equipment and Techniques (1) Epidemiologic and Genetic Studies (2) Preoperative (1) In Diabetes Mellitus (1) In Thalassemia (1) Physical Fitness (1) Bronchoscopy (7)

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 169. pp 254–264, 2004 DOI: 10.1164/rccm.2312010 Internet address: www.atsjournals.org

The precise role of menopause as a risk factor for sleep-disordered breathing is unclear. To determine the association of premenopause, perimenopause, and postmenopause with sleep-disordered breathing, Young and coworkers (1) studied a population-based sample of 589 women enrolled in the Wisconsin Sleep Heart Study. Compared with premenopausal women, postmenopausal women were 2.6 times more likely to have 5 or more apneas and hypopnea events per hour (during polysomnography in a laboratory) and 3.5 times more likely to have 15 or more apnea and hypopnea events per hour. The risk of sleep-disordered breathing was not increased among perimenopausal women. The authors conclude that the transition to menopause is associated with an increased risk of sleep-disordered breathing. An editorial commentary by White (2) accompanies this article. In a sample of 2,852 women, 50 years or older, participating in the Sleep Heart Health Study, Shahar and coworkers (3) asked, “Does hormone-replacement theory alter the risk of sleep-disordered breathing”? An apnea–hypopnea index of 15 events or more per hour (during unattended, single-night polysomnography at home) was observed in 6.7% of the 907 hormone users and in 14.7% of the 1,945 nonusers. After adjusting for confounding variables, hormone use was inversely related to sleep-disordered breathing in various subgroups, and was especially strong in 50to 59-year-old women (adjusted odds ratio, 0.36). The authors conclude that hormone replacement therapy may prevent or alleviate sleep-disordered breathing in postmenopausal women. An editorial commentary by White (2) accompanies this article. To determine whether obstructive airways disease is associated with sleep-disordered breathing, Sanders and coworkers (4) analyzed polysomnography and spirometry data from 5,954 participants in the Sleep Heart Health Study. Obstructive airway disease, defined as FEV1/FVC ratio of less than 70%, was present in 1,132 participants; involvement was mostly mild (FEV1/FVC, 63.8%). A respiratory disturbance index of greater than 10 events per hour was equally prevalent in subjects with obstructive airway disease and in subjects without obstructive airway disease, 22.3 versus 28.9%. In subjects without sleep apnea–hypopnea, the adjusted odds ratio for sleep desaturation (more than 5% of sleep time with saturation below 90%) exceeded 1.9 when FEV1/FVC was less than 65%. The authors conclude that mild obstructive airways disease is not associated with sleep apnea– hypopnea, although an FEV1/FVC of less than 65% is associated with sleep desaturation. An editorial commentary by Fleetham (5) accompanies this article.

Year in Review

Risk Factors

Arterial hypertension, a common finding in patients with sleep apnea, is the main risk factor for aortic dissection. To investigate the relationship between aortic dissection and obstructive sleep apnea syndrome, Sampol and coworkers (6) studied 19 consecutive patients with thoracic aortic dissection and 19 matched patients with hypertension. An apnea–hypopnea index of more than 5 events per hour was observed in 13 patients (68%) from each group. The average apnea–hypopnea index was greater in the aortic dissection group than in the control group: 28 versus 11 events per hour. An apnea–hypopnea index of more than 30 events per hour was noted in 7 of the patients with aortic dissection versus 1 of the patients with hypertension. The authors conclude that patients with thoracic aortic dissection have a high prevalence of obstructive sleep apnea syndrome. Pathophysiology

Cardiovascular mechanisms. Sleep-disordered breathing is associated with altered output of the autonomic nervous system. To determine whether obstructive and central apneas have different effects on the autonomic nervous system, Spicuzza and coworkers (7) studied 17 patients with sleep-disordered breathing. Cyclic alterations in the R-R interval occurred with both types of apneas. The mean R-R interval was longer during obstructive apneas than during central apneas: 1,011 versus 893 ms. During obstructive apneas, high-frequency oscillations were higher during apneas than during postapneic hyperventilation (1,964 versus 387 ms2), whereas low-frequency oscillations were lower during apnea than during postapneic hyperventilation (2,649 versus 9,820 ms2). (On the Wigner-Ville transform of power spectral analysis, the low-frequency components of interbeat interval reflect sympathetic modulation, and the high-frequency components reflect parasympathetic modulation.) During central apneas, high-frequency oscillations were lower during apneas than during postapneic hyperventilation (452 versus 1,485 ms2), whereas low-frequency oscillations did not differ between the two phases. The authors conclude that alterations in the autonomic nervous system differ between central and obstructive apneas, and that the pattern supports a surge in sympathetic activity during the hyperventilation that follows an obstructive apnea. Jo and coworkers (8) developed a model-based approach for assessing autonomic control of heart rate. During the application of continuous positive airway pressure (CPAP) in 9 patients with obstructive sleep apnea and in 8 healthy subjects, random modulation in inspiratory pressures was used to increase variability in respiratory and cardiovascular signals. Compared with the healthy subjects, the patients had a lower respiratory-cardiac coupling gain (36.9 versus 66.1 milliseconds per liter) and a lower baroreflex gain (2.3 versus 4.9 milliseconds per mm Hg). On falling asleep, the healthy subjects experienced a two- to threefold increase in baroreflex gain, whereas the patients showed little change. The authors conclude that the model provides an improved method for assessing autonomic function in patients with sleep apnea, and the findings provide further evidence that parasympathetic activity is reduced and sympathetic activity increased in patients with obstructive sleep apnea. In patients with congestive heart failure, Cheyne-Stokes respiration is accompanied by oscillations in blood pressure and heart rate at a very low frequency. To investigate whether the cardiovascular oscillations are primarily related to oscillations in ventilation or oxygen saturation, Leung and coworkers (9) studied 10 patients with heart failure and Cheyne-Stokes respiration during sleep. During Cheyne-Stokes respiration, heart rate and blood pressure oscillated in association with respiratory oscillation at very low frequency. Inhalation of carbon dioxide abol-

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ished the Cheyne-Stokes respiration and the associated oscillations in both blood pressure and heart rate. Inhalation of oxygen sufficient to eliminate dips in oxygen saturation had no effect on Cheyne-Stokes respiration, blood pressure, or heart rate. The authors conclude that oscillations in ventilation during CheyneStokes respiration, rather than oscillations in oxygenation, induce oscillations in heart rate and blood pressure. T cells have two distinct lineages: those expressing ␣␤ T cell receptors and those expressing ␥␦ T cell receptors. Less than 5% of circulating lymphocytes consists of ␥␦ T cells, but their unique migration, cytotoxic features, and accumulation is atherosclerotic plaques implicates them in cardiovascular disorders. To assess the potential involvement of circulatory ␥␦ T lymphocytes in endothelial cell damage in obstructive sleep apnea, Dyugovskaya and coworkers (10) characterized the phenotype, cytokine profile, adhesion properties, and cytotoxicity of ␥␦ T cells in 34 patients with obstructive sleep apnea and 19 control subjects. Expression of the inhibitory natural killer B1 receptors was greater in patients than in control subjects. Intracellular content of proinflammatory cytokines, tumor necrosis factor-␣ and interleukin-8, was greater in the patients than in the control subjects, and the anti-inflammatory cytokine, interleukin-10, was less. ␥␦ T cells of patients adhered more avidly to nonactivated endothelial cells in culture than did those of control subjects. Expression of lselectin in ␥␦ T cells was higher in patients. The adhesion index of ␥␦ T lymphocytes/endothelial cells was decreased by antibodies directed against E/P-selectin and tumor necrosis factor-␣ in the patients but not in the control subjects. Cytotoxicity of ␥␦ T lymphocytes against endothelial cells was greater in the patients than in the control subjects, and could be prevented by pretreatment with antibody against tumor necrosis factor-␣. The authors conclude that ␥␦ T cells of patients with obstructive sleep apnea express increased inhibitory natural killer B1 receptors, increased proinflammatory cytokines, and decreased anti-inflammatory cytokines, which predispose to endothelial cell injury and adverse cardiovascular function. Upper airway mechanisms. To determine whether upper airway anatomy is a risk factor for sleep apnea, Schwab and coworkers (11) used magnetic resonance imaging and computer reconstruction algorithms to obtain three-dimensional volumetric measurements. Measurements were obtained in 48 patients with sleep apnea (apnea–hypopnea index, 44 events per hour) and 48 control subjects (apnea–hypopnea index, 2 events per hour), matched for sex and ethnicity. The volumes of the lateral pharyngeal walls, tongue, and total soft tissue were greater in the patients than in the healthy subjects. After adjustment for covariates, the risk of sleep apnea was associated with total lateral pharyngeal wall volume (odds ratio, 6.01), total tongue volume (odds ratio, 4.66), and total soft tissue volume (odds ratio, 6.95). In multivariable logistic regression, the volume of the tongue and volume of the lateral walls were independently associated with the risk for sleep apnea. The authors conclude that the volumes of the tongue, total soft tissue, and lateral pharyngeal walls are increased in patients with sleep apnea and are important risk factors for the development of apneas. An editorial commentary by Sanders (12) accompanies this article. To delineate the upper airway in children with sleep apnea, Arens and coworkers (13) did magnetic resonance and automatic segmentation in 20 children with obstructive sleep apnea and 20 control children. Compared with the control group, the children with sleep apnea had smaller airway volume (1,129 versus 1,794 mm3), and smaller mean cross-sectional area (28 versus 47 mm2) and smaller minimal cross-sectional area (4.6 versus 15.7 mm2) of the total airway. Segmental analysis revealed restriction throughout the initial two-thirds of the upper airway rather than in discrete regions adjacent to the adenoids or tonsils.

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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 169 2004

Regional analysis revealed that the area was most restricted where the adenoids and tonsils overlapped. The authors conclude that the upper airway in children with obstructive sleep apnea has less volume and is narrower than in healthy children, and that restriction occurs throughout the initial two-thirds of the airway and is greatest where the adenoids and tonsils overlap. To determine the role of the upstream segment of the upper airway in the development of upper airway collapsibility, Farre and coworkers (14) studied 10 patients (apnea–hypopnea index, 59 events per hour) while they breathed air or helium-oxygen during non-REM sleep. The level of CPAP that normalized flow was lower while breathing helium-oxygen as compared with air: 8.4 versus 10.2 cm H2O. Upstream resistance was lower while breathing helium-oxygen as compared with air: 9.2 versus 15.9 cm H2O per liter per second. Critical pressure was equivalent with helium-oxygen and air: 4.9 versus 4.2 cm H2O. The authors conclude that the upstream segment of the upper airway plays an important role in the airway obstruction of sleep apnea. Using acoustic reflection, Izci and coworkers (15) measured the upper airway dimension in 50 women in third trimester of pregnancy, 37 women with pre-eclampsia, and 50 nonpregnant women. Snoring was reported by 14% of the nonpregnant women, 28% of the pregnant women, and 75% of the pre-eclamptic women. In the seated position, oropharyngeal junction area was less in pre-eclamptic women (0.9 cm2) than in nonpregnant women (1.1 cm2) or pregnant women (1.3 cm2). In the supine position, oropharyngeal junction area was less in pre-eclamptic women (0.8 cm2) than in nonpregnant women (1.0 cm2) but equivalent to that in pregnant women (0.9 cm2). The authors conclude that women with pre-eclampsia have narrowing of the upper airway in both the upright and supine posture. Whether or not sleep apnea can or cannot be viewed as an anatomic disorder is debated by Schwab (16) and Strohl (17), with rebuttals from each (18, 19). Control of breathing. Severity of obstructive apneas may be related to mechanical properties of the passive upper airway and/or impairment of control mechanisms during sleep. Younes (20) studied the contribution of these factors in 82 patients (range of apnea–hypopnea index, 2 to 146 events per hour). During rapid dial down of CPAP to near atmospheric pressure, the lowest inspiratory flow rate was taken as an index of passive collapsibility; the minimum effective level of CPAP was taken to reflect the pressure that the upper airway dilators needed for generating stable breathing. The index of passive collapsibility was greater in men and obese patients. The minimum effective level of CPAP was higher in men, supine position, older patients, and obese patients. Mechanical load accounted for only 34% of the variability in severity of obstructive apneas. At a given mechanical load, severity was greater in the supine position and during REM, but independent of age, sex, and body mass index. Periods of stable breathing were experienced by 82% of patients. The author concludes that most patients with obstructive sleep apnea can mount effective compensation to an elevated mechanical load, at least part of the time, and that differences in mechanical load account for about a third of the variability in severity of apneas. An editorial commentary by Naughton (21) accompanies this article. Because sleep apnea is commoner in men than in women, Jordan and coworkers (22) studied the ventilatory response to arousal in 13 healthy men and 13 healthy women. At sleep onset, men and women exhibited an equivalent decrease in ventilation and equivalent increases in upper airway resistance and endtidal CO2. Spontaneous arousal (lasting 6.6 seconds) caused a biphasic ventilatory response: hyperventilation lasting 5 seconds followed by hypoventilation for 30 to 40 seconds on resumption of sleep. The biphasic ventilatory response to arousal was greater in men than in women, and was not explained by differences in

wake-to-sleep increases in CO2 or differences in upper airway resistance. Peripheral vasoconstriction (measured as pulse wave amplitude on finger photoplethysmography) with arousal was greater in men than in women. Ventilatory responses were more marked after tone-induced arousals than after spontaneous arousals, and also when subjects slept in the supine position than when they slept in the left lateral position. The authors conclude that the ventilatory response and instability after arousal is greater in men than in women and also greater in the supine than in the left lateral position. Intermittent hypoxia during sleep induces significant neurobehavioral deficits in rats. To determine whether expression and activity of cyclogenase-2 (which is induced by cerebral ischemia) contributes to the development of neurobehavioral deficits, Li and coworkers (23) examined the cortical regions of rat brain after exposure to either intermittent hypoxia (10% oxygen alternating with 21% oxygen every 90 seconds) or sustained hypoxia (10% oxygen). Intermittent hypoxia induced an increase in cyclooxygenase-2 protein and gene expression between the first and fourteenth day of exposure. Expression of the gene for cyclooxygenase-1 was not affected by hypoxia. Upregulation of cyclooxygenase-2 in response to intermittent hypoxia was associated with increased tissue levels of prostaglandin E2, neuronal apoptosis, and neurobehavioral deficits. Selective inhibition of cyclooxygenase-2 with NS-398 attenuated the deficits in acquisition and retention of a spatial task (in a water maze) induced by intermittent hypoxia. The authors conclude that intermittent hypoxia induces upregulation and activation of cyclooxygenase-2 in rat cortex and that this enzyme may modulate the neurobehavioral deficits induced by chronic hypoxia. Because ventilatory sensitivity to hypoxia may influence the degree of hypoxic stress and sleep disruption, Rubin and coworkers (24) studied the effect of sleep-induced hypoxia and sleep fragmentation in two strains of mice: one strain (A/J) with low and one strain (DBA/2J) with high ventilatory sensitivity to hypoxia. Compared with the DBA/2J mice, sleep-induced hypoxia in the A/J mice (with low hypoxic sensitivity) resulted in a greater time to arousal (26.4 versus 21.3 seconds), more hypoxic events (640 versus 368 events per 24 hours), and greater sleep time (47.5 versus 26.5% per 24 hours). Sleep fragmentation without hypoxia produced an equivalent event characteristics and total sleep time in the two strains. Time to arousal during both sleep-induced hypoxia and sleep fragmentation was longer during the light phase than during the dark phase for both strains. The authors conclude that genetic background influences respiratory events and sleep architecture during induced hypoxia and that the threshold for arousal to a hypoxic stimulus was highest during the light phase of sleep. Cherniack (25) recalls early studies of periodic breathing. Clinical Aspects

In critically ill patients. To determine the prevalence of noise in the ICU and its effect on sleep, Gabor and coworkers (26) did polysomnography on seven mechanically ventilated patients and six healthy subjects over 24 hours in the ICU. Time-synchronized environmental monitoring was also performed. The average level of noise was 51 dB in the open ICU and 43 dB in an isolated single room. (Noise in a busy office is 70 dB, and 40 dB in a bedroom.) In the patients, increases in sound occurred 37 times per hour of sleep and were responsible for 21% of all arousals and awakenings. Patient-care activities occurred 8 times per hour and were responsible for 7% of all arousals and awakenings. Compared with an open ICU, healthy subjects slept longer when placed in a single ICU room (9.5 versus 8.2 hours); sleep architecture was not altered. The authors conclude that noise and pa-

Year in Review

tient-care activities account for 28% of arousals and awakenings in critically ill patients receiving mechanical ventilation. In children. To determine whether snoring is associated with poor academic performance in third-grade school children (mostly 9-year-olds), Urschitz and coworkers (27) studied 1,444 children by questionnaire and nocturnal home oximetry. Poor academic performance was a score of 4 to 6 (lowest quintile) on a 6-point scale (1 for outstanding, and 6 for failed). Snoring reported as “always” was associated with poor performance in mathematics (odds ratio, 3.6), science (odds ratio, 4.3), and spelling (odds ratio, 3.5). Snoring reported as “frequent” was associated with poor performance in mathematics (odds ratio, 2.4) and spelling (odds ratio, 2.0). Intermittent hypoxia did not show an independent association with poor academic performance. The authors conclude that habitual snoring is associated with poor academic performance in third-grade school children. In 10 children with obstructive sleep apnea (apnea–hypopnea index, 8 events per hour) and 6 healthy children, Katz and White (28) studied genioglossus activity (intraoral surface electromyography) during wakefulness and sleep onset. During wakefulness, genioglossus activity was greater in patients than in control subjects (3.6 versus 1.6% of maximum). The decline in genioglossus activity during early and late sleep onset was greater in the patients. During stable non-REM sleep, activity of the genioglossus remained below the baseline value for wakefulness in all of the control children, but increased above baseline in 4 of the 10 children with sleep apnea. The authors conclude that children with obstructive sleep apnea display increased activity of the genioglossus during wakefulness, probably as compensation for deficient pharyngeal anatomy. To determine the characteristics of arousal from sleep in infants who eventually die from sudden infant death syndrome (SIDS), Kato and coworkers (29) analyzed recordings obtained in 16 infants who had been studied some days or weeks before dying from SIDS. Compared with a control group of infants, the infants who later died of SIDS had less frequent cortical arousals (complete arousals) during both REM sleep (14.3 versus 23.1 per hour of sleep) and non-REM sleep (3.1 versus 3.6 per hour of sleep). Compared with the control group, the infants who later died of SIDS had more frequent subcortical activations (body movement without EEG change) during REM sleep (4.0 versus 1.4 per hour of sleep). The duration of subcortical activations was greater in the infants who later died of SIDS than in the control group (median duration, 7 versus 5 seconds). Compared with the control group, the infants who later died of SIDS had more frequent subcortical activations in the first part of the night (from 9:00 p.m. to 12:00 a.m.) and fewer cortical arousals during the later part of the night (from 3:00 a.m. to 6:00 a.m.) The authors conclude that infants who die from SIDS exhibit incomplete arousal processes during sleep in the weeks or months before their death. An editorial commentary by Harper (30) accompanies this article. Diagnostic Techniques

To determine the reliability of a decision rule in identifying patients with obstructive sleep apnea, Tsai and coworkers (31) measured respiratory disturbance index in 75 consecutive patients using a portable monitor. A decision rule was developed based on three predictors: a cricomental space of 1.5 cm or less, a pharyngeal grade of more than II, and the presence of overbite. Seventeen percent of patients had all three predictors. When all three predictors were present, the positive predictive value for obstructive sleep apnea (respiratory disturbance index of at least 10 events per hour) was 95%. The absence of all three predictors did not exclude sleep apnea: the negative predictive value was 49%. A cricomental distance of more than 1.5 cm excluded sleep apnea

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(negative predictive value 100%). Comparable performance was achieved in a validation sample of 50 patients. The authors concluded that a new decision rule provides a simple and reliable way of identifying patients with and without obstructive sleep apnea. Treatment

Airway pressure and flow. To determine whether patients can effectively titrate their own CPAP setting, Fitzpatrick and coworkers (32) did a randomized crossover trial in 18 newly diagnosed patients (aged 50 years, with an apnea–hypopnea index of 40 events per hour). The setting of CPAP based on overnight polysomnography in a laboratory was 9.7 cm H2O. The level of CPAP based on a prediction formula and self-adjustment to maximum comfort and perceived efficacy was 10.1 cm H2O. After 5 weeks, both modes of CPAP achieved equivalent improvements in functional outcome, sleep apnea severity, sleep architecture, maintenance of wakefulness tests, and quality of life. The authors conclude that self-titration of CPAP is as effective as laboratory-set CPAP in improving objective and subjective assessments of sleep apnea. An editorial commentary by Kuna (33) accompanies this article. To determine whether correction of the disturbed breathing pattern in patients with Cheyne-Stokes respiration can decrease excessive daytime sleepiness (that likely results from sleep fragmentation), Pepperell and coworkers (34) did a randomized parallel trial in 30 patients. The patients had an apnea–hypopnea index of 19.8 events per hour, and heart failure of Class II to IV severity (staging of New York Heart Association). Patients were randomized to adaptive servoventilation delivered at a therapeutic or subtherapeutic level during the night for 1 month. When delivered at a therapeutic level versus a subtherapeutic level, adaptive servoventilation caused a decrease in excessive daytime sleepiness (difference of 8.9 minutes on Osler test), accompanied by a 23% decrease in brain natriuretic peptide (a marker of cardiac loading) and a 25% decrease in urinary metadrenaline. The authors conclude that nighttime use of adaptive servoventilation produces an improvement in excessive daytime sleepiness, accompanied by improvement in neurohormonal activation. To determine whether autotitration of CPAP is more effective than a fixed pressure determined in a laboratory, Massie and coworkers (35) did a 6-week randomized, single-blind, crossover study. The study was done in 44 patients with an apnea–hypopnea index of 15 or more and who required CPAP of 10 cm H2O or higher. Compared with the fixed setting of CPAP, autotitration of CPAP resulted in greater nightly use (306 versus 271 minutes) and lower median pressure (6.9 versus 10.7 cm H2O). Compared with fixed CPAP, the autotitrating device achieved a higher SF-36 vitality score (65 versus 58) and a higher mental health score (80 versus 75), but no difference in the Epworth sleepiness score. Patients reported more restful sleep, better quality sleep, less discomfort from pressure, and less trouble getting to sleep with the autotitrating device. The authors conclude that an autotitrating CPAP device achieves greater benefit than does a fixed level of CPAP in patients who require a setting of 10 cm H2O or higher. In 29 patients with obstructive sleep apnea (apnea–hypopnea index, 46 events per hour), Senn and coworkers (36) did a randomized comparison of three CPAP systems. Patients were randomized to each system for three consecutive periods, each lasting one month. The DeVilbiss AutoAdjust LT system is an autoCPAP device that responds to apnea–hypopnea and snoring. The AutoSet T system is an autoCPAP device that responds to apnea–hypopnea, snoring, and changes in inspiratory flow contour. The third system consisted of fixed CPAP, set at the 90th percentile of pressure titrated by autoCPAP over 2 weeks. The

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three systems produced equivalent improvements in symptoms, quality of life, and apnea–hypopnea index. Compared with baseline, increases in maintenance-of-wakefulness time were 4.5 minutes for the DeVilbiss system, 6.0 minutes for the AutoSet T system, and 6.1 minutes for fixed-pressure CPAP. The authors conclude that two autoCPAP systems (DeVilbiss and AutoSet T) were equally effective as a fixed-pressure CPAP system in improving apnea–hypopnea index, quality of life, and vigilance in patients with sleep apnea. Pharmacotherapy. To determine whether physostigmine, a cholinesterase inhibitor, decreases the severity of sleep-disordered breathing, Hedner and coworkers (37) did a double-blind trial in 10 men with severe obstructive sleep apnea (apnea– hypopnea index of 54 events per hour and minimum oxygen saturation of 74%). Compared with placebo, an infusion of physostigmine (over 7 hours) produced a 21% decrease in apnea– hypopnea index and a 23% increase in the minimum level of oxygen saturation. During the last third of the night (when physostigmine is in steady state), physostigmine decreased REM-associated apnea–hypopnea index by 68%. Total sleep time was reduced by 74 minutes, and patients with the least reduction in sleep time had the largest reduction in apnea–hypopnea index (r ⫽ 0.73). Physostigmine decreased the nocturnal decline in heart rate. The early-night, resting heart rate (on placebo night) was positively correlated with the decrease in apnea–hypopnea index associated with REM (r ⫽ 0.69). The authors conclude that physostigmine decreases the number of obstructive apnea events, primarily during REM sleep. The role of modafinil in the management of sleep apnea is debated by Black (38) and Pollak (39), with rebuttals from each (40, 41). In an occasional essay, Pack (42) discusses whether a pharmacologic agent should be approved for the broad indication of excessive sleepiness. Mandibular devices. The precise mechanism whereby oral appliances achieve improvement in obstructive sleep apnea is not known. To investigate the effect on upper airway collapsibility, Ng and coworkers (43) studied 10 patients with obstructive sleep apnea treated with a custom-made mandibular advancement splint. During an acclimatization period, the splint was incrementally adjusted to achieve the greatest anterior advance of the mandible that was comfortable; polysomnography was then performed to document efficacy. Patients underwent no treatment for 1 week, and polysomnography was again performed. Compared with no therapy, the mandibular advancement splint decreased the apnea–hypopnea index (13 versus 25 events per hour), and decreased collapsibility of the upper airway: upper airway closing pressures of ⫺3.9 versus ⫺1.6 cm H2O during Stage 2 sleep and ⫺4.7 versus ⫺2.5 cm H2O during slow-wave sleep. Change in apnea–hypopnea index was correlated with change in upper airway closing pressure during Stage 2 sleep (r ⫽ 0.64). The authors conclude that a mandibular advancement sleep decreases collapsibility of the upper airway during sleep. Surgery. Laser-assisted uvulopalatoplasty is an outpatient surgical alternative to uvulopalatopharyngoplasty. Ferguson and coworkers (44) did a randomized trial of the laser surgery in 45 patients with mild obstructive sleep apnea (apnea–hypopnea index of 10 to 27 per hour). Laser surgery caused a 21% decrease in apnea–hypopnea index; the index decreased to 10 or less per hour in 5 of the 21 patients (24%). The index decreased to 10 or less per hour in 4 of the 24 subjects in the control group (16.7%). Ten patients (48%) reported significantly less snoring after laser surgery. The surgery produced a small improvement in quality of life, but no change in excessive daytime sleepiness. Side effects were common, but serious complications did not occur. The authors conclude that laser-assisted uvulopalatoplasty de-

creases snoring in some patients with mild obstructive sleep apnea but the reduction in apnea-hypopnea index is mild. Obesity management. In a clinical commentary, Foster (45) discuss the management of obesity.

CONTROL OF BREATHING Studies in Animals

In anesthetized adult rats, Fenik and Veasey (46) studied the role of serotonin receptor subtypes in the excitation of neurons of the upper airway dilator muscles. The dose responses of agonists and antagonists injected into the hypoglossal nucleus were determined. An antagonist against serotonin receptor subtype 2A decreased intrinsic respiratory activity in the hypoglossal nerve by 61%, and suppressed serotonin excitation of the nerve. An antagonist against serotonin receptor subtype 2C decreased hypoglossal nerve activity by 17%, and suppressed the dose– response for the 2C agonist. Excitatory effects of the serotonin 2C agonist were of low magnitude and associated with rapid desensitization. An antagonist against serotonin receptor subtype 7 had no effect on either intrinsic activity or agonist responses. The authors conclude that serotonin 2A is the predominant excitatory serotonin receptor subtype of the hypoglossal motor neurons. To determine whether prenatal hypoxia leads to sustained modifications in ventilatory control and impairs the ability to learn a spatial task, Gozal and coworkers (47) exposed pregnant rats to intermittent hypoxia (10% oxygen concentration alternating with 21% oxygen every 90 seconds) or room air. At 5, 10, 15, and 30 days after delivery, newborn rats exposed to prenatal hypoxia had higher normoxic ventilation than did newborn rats exposed to prenatal room air. The peak ventilatory response to hypoxia at 5 days of age was depressed in rats exposed to prenatal hypoxia. Ventilatory equivalent (minute ventilation in relation to oxygen consumption) was decreased in rats exposed to prenatal hypoxia. The learning and memory of spatial tasks at one and four months was similar in rats exposed to prenatal hypoxia or normoxia. The authors conclude that gestational intermittent hypoxia leads to prolonged and irreversible alterations in respiratory control but does not produce obvious neurocognitive impairment. Exposing an adult rat to intermittent hypoxia results in neurobehavioral impairment and increased apoptosis in the hippocampal CA1 region and cortex. In adult rats, Row and coworkers (48) examined whether intermittent hypoxia induces lipid peroxidation in cortical tissue and whether the latter is associated with neurocognitive impairment. Exposing adult rats to intermittent hypoxia (alternating 90-second periods of 10% oxygen and 21% oxygen) caused impairment of the ability to learn a spatial task (in a water maze). Twice-daily treatment with an antioxidant (PNU-101033E) attenuated the impairment in spatial learning. The antioxidant also attenuated the increase in lipid peroxidation and isoprostane concentration associated with intermittent hypoxia. The authors conclude that exposure to intermittent hypoxia induces oxidative stress, which is associated with behavioral impairment. Pathophysiological Studies in Volunteers

When mechanical ventilation is delivered under normocapnic conditions, its cessation is accompanied by central apneas. To determine whether increases in tidal volume or increases in respiratory rate are responsible for the change in respiratory rhythm, Rice and coworkers (49) increased tidal volume (to 135 to 220% of eucapnic volume) and respiratory rate (1 or 3 breaths above eucapnic rate) in 7 healthy subjects during NREM sleep. During controlled ventilation, an increase in tidal volume (by 65% or more of eucapnic volume) plus an increase in rate (of 1 breath per

Year in Review

minute) eliminated transdiaphragmatic pressure. Cessation of controlled ventilation was accompanied by prolongation of expiratory time (by 2 to 4 times the control value); the increases in expiratory time were proportional to the increases in tidal volume during controlled ventilation but were independent of further increases in ventilator rate. During and after assist-control ventilation, increases in tidal volume (to 135 to 220% of eucapnic volume) were accompanied by decreases in transdiaphragmatic pressure in proportion to the increase in tidal volume; each ventilator inflation was actively triggered and the increase in expiratory time on cessation of mechanical ventilation was less than 20% of that seen after cessation of controlled ventilation. The authors conclude that both increases in ventilator rate and delivered volume during mechanical ventilation cause inhibition of respiratory motor output via nonchemical mechanisms (neuromechanical effects of repeated and augmented lung inflation), and that the resetting of respiratory rhythm is greater with additional increase in ventilator rate than with increase in delivered volume alone. In 11 healthy men performing cycle exercise, Fukuoka and coworkers (50) investigated the contributions of hypoxic ventilatory responsiveness, hypercapnic ventilatory responsiveness, and other factors in the stimulus responsible for exercise hyperpnea during hypoxia. Exercise was performed at an oxygen concentration of 12% at three constant work rates (40%, 60%, and 80% of a subject’s ventilatory threshold at hypoxia). Compared with normoxia, hypoxic ventilatory responsiveness was increased during hypoxia, and then increased in proportion with the increase in work rate. In contrast, hypercapnic ventilatory responsiveness was unaffected by the difference in work rate at hypoxia, but it did exceed the level of responsiveness during normoxia. The decrease in the half-time of hypoxic ventilation became significant with an increase in work rates and was lower than at normoxia. Hypoxic ventilatory responsiveness accounted for 63% of the variance of hypoxic ventilatory dynamics at the onset of exercise and hypercapnic ventilatory responsiveness accounted for 9%. On-kinetics and off-kinetics of oxygen uptake were slower under hypoxic conditions than under normoxic conditions, but were not altered by changing work rates during hypoxia. The authors conclude that the faster hypoxic ventilatory dynamics at the onset of exercise can be attributed mostly to augmentation of hypoxic ventilatory responsiveness with increases in work rates rather than to hypercapnic ventilatory responsiveness. The ventilatory response to hypoxia in the presence of hypocapnia is controversial. Corne and coworkers (51) used volumecycled ventilation to measure the ventilatory response to hypoxia during eucapnia and hypocapnia. The response of respiratory muscle pressure to hypoxia (expressed as cm H2O per percentage oxygen saturation) was 0.53 at eucapnia, 0.26 at end-tidal Pco2 of 6 mm Hg below eucapnia, and 0.003 at Pco2 of 12 mm Hg below eucapnia. Similar reductions were evident for respiratory rate (expressed as breaths per minute per percentage oxygen saturation): 0.17 at eucapnia, 0.11 at Pco2 of 6 mm Hg below eucapnia, and 0.01 at Pco2 of 12 mm Hg below eucapnia. The responses of respiratory muscle pressure and respiratory rate at a Pco2 of 12 mm Hg below eucapnia were not significantly different from zero. The authors conclude that regardless of the strength of the hypoxic ventilatory response at eucapnia, the responses are lost when Pco2 is reduced (in a stable manner) by 6 to 12 mm Hg below eucapnia. Control of Breathing in Clinical Disorders

Short-term potentiation is a mechanism in the brain stem that promotes breathing stability and prevents healthy subjects from hypoventilating in the period immediately after a hypoxic challenge. Because short-term potentiation appears impaired in pa-

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tients with brain damage, Mitrouska and coworkers (52) determined whether theophylline would improve breathing stability in these patients. Brief exposure (45 seconds) to hypocapnic hypoxia produced similar increases in ventilation in 8 stable patients with brain damage and in 10 healthy subjects. In the healthy subjects, inhalation of a hyperoxic gas at the end of the hypoxic challenge was accompanied by a decline in ventilation without a ventilatory undershoot (indicating activation of shortterm potentiation); the response was equivalent for placebo and theophylline. In the patients, inhalation of a hyperoxic gas at the end of the hypoxic challenge was accompanied by a significant ventilatory undershoot when the patients received placebo. The undershoot in the patients was attenuated, but not prevented, by theophylline. The authors conclude that theophylline largely prevents the ventilatory undershoot that occurs in patients with brain damage during the recovery period after hypoxic stimulation, and the effect is probably mediated through activation of short-term potentiation. Familial dysautonomia, Riley-Day syndrome, affects the central and peripheral autonomic nervous systems. In 22 patients with familial dysautonomia and 23 healthy subjects, Bernardi and coworkers (53) studied the respiratory, cardiovascular, and cerebrovascular responses to isocapnic hypoxia and hyperoxic hypercapnia. Compared with the control group, the patients had elevated end-tidal carbon dioxide tension, lower oxygen saturation, lower R-R interval, and higher blood pressure. Baseline ventilation was normal, and the respiratory and cardiovascular responses to hyperoxic hypercapnia were normal in the patients. Progressive isocapnic hypoxia resulted in blunted increases in ventilation, paradoxical decreases in R-R interval and blood pressure, and lack of increase in midcerebral artery flow velocity. Hyperventilation induced longer apneic spells (52 versus 11 seconds) with profound desaturation (76%), marked hypotension, and increase in R-R interval. The authors conclude that patients with familial dysautonomia develop central depression in response to even moderate hypoxia with lack of expected change in the cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially to respiratory arrest.

RESPIRATORY MUSCLES Studies in Animals

Mechanical ventilation. In rats, Racz and coworkers (54) studied the effects of 24 hours of mechanical ventilation on muscle protein and transcription factors at the levels of both messenger RNA and protein. The diaphragm of ventilated rats exhibited decreases in messenger RNA of MyoD, myosin heavy chain-2a and 2b, and sarcoplasmic/endoplasmic reticulum calcium-ATPase-1a; messenger RNA of myogenin was increased. Protein expression of MyoD and myogenin followed the changes in messenger RNA; isoforms of myosin heavy chains did not change. Parallel experiments on the gastrocnemius revealed that immobilization induced deconditioning; passive shortening induced no additional effects. The two muscles exhibited a similar pattern of change with the exception of protein expression of MyoD, which increased in the gastrocnemius and decreased in the diaphragm (messenger RNA decreased in both muscles). The authors conclude that controlled mechanical ventilation alters the levels of messenger RNA for muscle heavy chain isoforms and sarcoplasmic/endoplasmic reticulum calcium ATPase isoforms within 24 hours. Pathophysiological Studies in Patients and Volunteers

Exercise and peripheral muscles. To determine whether the development of quadriceps fatigue during exercise influences the response to a bronchodilator, Saey and coworkers (55) studied

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18 patients with chronic obstructive pulmonary disease (COPD) (FEV1, 38% predicted). Compared with placebo, inhalation of ipratropium bromide (500 ␮g) tended to increase the time that cycle exercise was endured at a constant work rate: 440 versus 322 seconds. Nine patients developed quadriceps fatigue (a decrease in quadriceps twitch pressure of more than 15%) secondary to exercising after placebo; ipratropium did not increase endurance time in these patients despite an increase in FEV1 of 11%. Nine patients did not develop quadriceps fatigue secondary to exercising after placebo; ipratropium increased endurance time in these patients (479 versus 249 seconds). The improvement in endurance time with ipratropium was correlated with twitch force of the quadriceps at 10 minutes after exercise preceded by placebo (r ⫽ 0.59). The authors conclude that the development of quadriceps fatigue may explain why some patients with COPD fail to increase endurance time after ipratropium. An editorial commentary by Casaburi (56) accompanies this article. Oxidative stress arising in exercising muscle may contribute to the peripheral muscle dysfunction of COPD. To determine whether quadriceps exercise induces oxidative stress and whether the stress decreases muscle endurance, Couillard and coworkers (57) studied 12 patients with COPD (FEV1, 33% predicted) and 10 healthy subjects. Biopsies of the vastus lateralis were obtained before and 48 hours after exercise. Quadriceps endurance was less in the patients than in the control subjects: 378 versus 843 seconds. At 48 hours, patients, but not the control subjects, displayed increases in muscle lipid peroxidation and oxidized protein; the control subjects, but not the patients, displayed an increase in peroxidase glutathion activity. Endurance time was inversely correlated with both muscle lipid peroxidation (r ⫽ ⫺0.66) and oxidized protein (r ⫽ ⫺0.70). The authors conclude that quadriceps exercise increased oxidative stress but not antioxidant activity in patients with COPD, and the increase in oxidative stress was correlated with a decrease in quadriceps endurance. When cycling, patients with COPD often stop because of leg effort rather than dyspnea. To determine whether the response might differ when patients walk versus when they cycle, Man and coworkers (58) studied 84 patients with COPD (FEV1, 41% of predicted). Dyspnea alone was a more common limiting symptom during incremental walking than during incremental cycling (81 versus 34%) and during endurance walking than during endurance cycling (75 versus 29%). Twitch stimulation of the quadriceps was performed in 12 of the patients. Walking did not decrease twitch tension of the quadriceps, whereas cycling caused a 17.1% decrease in twitch tension. The authors conclude that leg effort and fatigue of the quadriceps are infrequent after walking in patients with COPD. To determine whether severity of COPD influences the degree of quadriceps fatigability after single muscle contractions, Mador and coworkers (59) studied 8 patients with severe COPD (FEV1, 26% predicted), 11 patients with mild-to-moderate COPD (FEV1, 50% predicted), and 10 healthy subjects. Maximum voluntary contraction of the right quadriceps achieved a force of 44 kg in severe patients, 49 kg in mild-to-moderate patients, and 58 kg in healthy subjects. Three sets of 10 maximum voluntary contractions of the quadriceps achieved greater fatigability (measured as the decrease in potentiated twitch force during magnetic stimulation of the femoral nerve) of the quadriceps in patients with severe COPD than in patients with mild-to-moderate COPD or the healthy subjects. The fall in twitch force in patients with mild-to-moderate COPD was not significantly different from healthy subjects. The authors conclude that patients with severe COPD display greater fatigability of the quadriceps muscle than do healthy subjects or patients with mild-to-moderate COPD.

To determine the pathophysiology of impaired exercise tolerance in patients with cystic fibrosis, Selvadurai and coworkers (60) studied 16 girls with mild cystic fibrosis (age 15 years) participating in elite sports and a control group of 16 female teammates without cystic fibrosis; FEV1 was respectively 96% and 98% of predicted. Compared with the control group, resting energy expenditure was 7.6% higher and habitual daily activity was 15% higher in the cystic fibrosis group. Peak aerobic capacity was equivalent in the two groups. Peak anaerobic power was 20% lower in the cystic fibrosis group. 31P magnetic resonance spectroscopy revealed no difference between the groups at rest. At 25% of total work output, the cystic fibrosis group was less acidotic than was the control group (pH 6.99 versus 6.90) and had a lower ratio of inorganic phosphorus to phosphocreatine (0.34 versus 0.41). The differences between the groups continued to increase until maximum exercise. The authors conclude that girls with mild cystic fibrosis who are exercising on a treadmill have intrinsic metabolic defects in skeletal muscle, decreased anaerobic power, and leg strength despite having normal lung function and good nutritional status. To determine the causes of exercise intolerance in patients with lymphangioleiomyomatosis, Taveira-DaSilva and coworkers (61) undertook cardiopulmonary exercise testing in 217 patients. Maximum oxygen uptake was decreased in 162 patients, of whom 28 did not reach anaerobic threshold, 29 patients had a low oxygen uptake at anaerobic threshold, and 54 developed hypoxemia. Maximum oxygen uptake decreased as the score for histologic severity increased. Significant predictors of maximum oxygen uptake were FEV1 and diffusing capacity for carbon monoxide; uptake was also correlated with computed tomography, use of oxygen, and resting Po2. Some patients with near normal FEV1 and diffusing capacity developed hypoxemia during exercise. The authors conclude that cardiopulmonary exercise testing should be performed in patients with lymphangioleiomyomatosis to determine the severity of abnormal gas exchange and the need for supplemental oxygen therapy. An editorial commentary by Sietsema and McCormack (62) accompanies this article. Chest wall motion. To investigate differences in movement of each side of the chest wall in patients with hemiplegia, Lanini and coworkers (63) measured tidal volumes of each hemithorax in eight men with hemiplegia (after cerebrovascular accidents) and nine healthy men using optoelectronic plethysmography. During quiet breathing, equivalent tidal volumes were achieved by the paretic (416 ml) and healthy hemithorax (403 ml). During voluntary hyperventilation, tidal volume was lower on the paretic side than on the healthy side: 582 versus 783 ml. During hypercapnic stimulation, tidal volume was higher on the paretic side than on the healthy side: 1,114 versus 805 ml. The authors conclude that patients with hemiplegia display smaller expansion of the paretic hemithorax than of the healthy hemithorax during voluntary hyperventilation (when breathing is under cortical control) and greater expansion of the paretic hemithorax during chemical stimulation (when breathing is under brainstem control). The volume of adult lungs is 10–12% smaller in women than in men of the same age and height. To evaluate how the difference in volume is distributed between rib-cage and diaphragmabdominal compartments, Bellemare and coworkers (64) obtained anteroposterior and lateral chest radiographs in 21 normal men and 19 normal women at three different lung volumes. Compared with men, women had smaller radial rib cage dimensions (in relation to height), greater inclination of ribs, shorter diaphragmatic length, and comparable position of the diaphragmatic dome relative to the spine at all lung volumes. During resting breathing, women exhibited greater contribution of the inspiratory rib cage muscles, presumably because the muscles had a

Year in Review

mechanical advantage arising from the greater anterior-posterior inclination of the ribs in women. A greater inclination of the ribs enabled the rib cage of women to accommodate a greater volume expansion. The authors conclude that women have a smaller rib cage and a shorter diaphragm than do men, in part because women have greater inclination of the ribs, and that the changes are well suited to accommodate the abdominal expansion of pregnancy. Diagnostic studies. Low levels of maximal expiratory pressure may arise from technical problems and not reflect expiratory muscle strength. To investigate the usefulness of measurements of gastric pressure during a cough, Man and coworkers (65) studied 293 patients referred for evaluation of respiratory muscle function and 99 healthy subjects. The coefficient of variation (with a subject on different occasions) was 6.9% for cough gastric pressure and 10.3% for mouth expiratory pressure in 24 of the healthy subjects. The mean cough gastric pressure was 214 cm H2O in healthy men and 165 cm H2O in healthy women. Among 171 patients deemed weak by measurements of mouth expiratory pressure, 42% had a normal cough gastric pressure. Among 105 patients deemed weak by measurements of cough gastric pressure, 6% had a normal mouth expiratory pressure. The authors conclude that low expiratory mouth pressure does not necessarily signify expiratory muscle weakness and that cough gastric pressure represents a useful complementary test. Respiratory muscle involvement in clinical disorders. To determine the relationship between respiratory and limb muscle mass, strength, and nutritional impairment, Pinet and coworkers (66) studied 18 patients with cystic fibrosis (mean age, 28 years) and 15 healthy subjects. Lean body mass, quadriceps strength, and quadriceps cross-section were lower in patients with cystic fibrosis. Twitch transdiaphragmatic pressure was 23% lower and twitch gastric pressure was 22% higher in the patients than in the control subjects. Diaphragmatic mass and abdominal muscle thickness were equivalent in the patients and control subjects. For any given lean body mass, however, diaphragmatic mass and abdominal wall thickness were greater in the patients than in the control subjects. Intersubject variability in diaphragmatic mass was greater in the patients than in the control subjects. The authors conclude that patients with cystic fibrosis have decreased muscle bulk of the quadriceps but not of the diaphragm and abdominal wall, and decreased strength of the diaphragm but increased strength of the abdominal muscles, suggesting a respiratory muscle training effect in at least some patients. An editorial commentary by Maltais (67) accompanies this article. To determine the relationship between diaphragmatic fiber type and severity of airway obstruction, Levine and coworkers (68) did biopsies of the costal diaphragm in 40 patients with COPD (FEV1 ranged from 16 to 118% of predicted). The relationship between the proportion of pure Type I fibers and FEV1 was exponential (r ⫽ 0.844): the proportion showed little increase as FEV1 decreased from 118 to 60% of predicted, but thereafter increased appreciably. Patients with severe COPD exhibited lower levels of maximal specific force in single fibers than did patients with normal lung function. Type I fibers generated lower force than did Type II fibers. The authors conclude that patients with COPD develop an increase of Type I fibers in their costal diaphragm when FEV1 falls below 60% of predicted and that force generation is also decreased secondary to adaptations within each fiber type. The adaptive response of inspiratory muscles to increased workloads includes increases in oxidative enzymes and changes in expression of contractile proteins, but the effect on mitochondrial function is not known. To study the in situ properties of mitochondria of respiratory muscles, Ribera and coworkers (69) obtained biopsies of the costal diaphragm and external intercostals in 9 patients with emphysema and in 11 control subjects.

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Maximal oxidative capacity was 135% higher in the diaphragm and 37% higher in the external intercostals in the patients than in the control subjects. Maximal oxidative capacity was correlated with percent predicted FEV1 (diaphragm: r ⫽ ⫺0.64; intercostals: r ⫽ ⫺0.67) and with the ratio of residual volume to total lung capacity (diaphragm: r ⫽ 0.64; intercostals: r ⫽ 0.63). The slow myosin heavy chain isoform was increased in the diaphragm of the patients. The authors conclude that maximal respiration of mitochondria is increased in both the diaphragm and external intercostal muscles of patients with emphysema, and that the associated improvement in the coupling of oxidation to phosphorylation suggests increased efficiency of ATP production by mitochondria. Laghi and coworkers (70) asked, “Do patients who fail a trial of weaning from mechanical ventilation develop diaphragmatic fatigue”? Transdiaphragmatic pressure was recorded during twitch stimulation of the phrenic nerves before and 30 minutes after completing a spontaneous breathing trial (lasting up to 60 minutes) in 11 weaning failure and 8 weaning success patients. Twitch transdiaphragmatic pressure was 8.9 cm H2O before the trials and 9.4 cm H2O after the trials in the weaning failure patients; the corresponding values in the weaning success patients were 10.3 and 11.2 cm H2O. The failure of twitch pressure to decrease in the weaning failure patients appears to have arisen because physicians interrupted the trial based on clinical manifestations of respiratory distress before patients had sufficient time to develop contractile fatigue. Weaning failure patients displayed increased recruitment of rib cage and expiratory muscles, and considerable diaphragmatic weakness. The authors conclude that patients failing a trial of weaning from mechanical ventilation do not develop low-frequency fatigue of the diaphragm, although many patients display severe diaphragmatic weakness. In a state of the art review article, Laghi and Tobin (71) discuss disorders of the respiratory muscles.

PULMONARY FUNCTION TESTING AND BRONCHOSCOPY Equipment and Techniques

Milic-Emili (72) recalls early studies on measurement of esophageal pressure. Epidemiologic and Genetic Studies

To identify chromosomal regions influencing pulmonary function, Wilk and colleagues (73) did a genome-wide scan on 391 pedigrees involving 2,178 individuals from the National Heart, Lung, and Blood Institute Family Heart Study. The genome scan identified three regions on chromosomes 4 and 18, with logarithm of the odds favoring linkage scores above 2.5. A locus on chromosome 4 in the region of D4S403 and D4S1511 showed linkage to the FEV1/FVC ratio. Two loci on chromosome 18, near D18S843 and near D18S851 and D18S858, were linked to both FEV1 and FVC, but not to FEV1/FVC ratio. The authors conclude that three loci meet established criteria for evidence of linkage in influencing variability of spirometric measures of lung function. To better understand the genetics underlying pulmonary function, Malhotra and coworkers (74) analyzed data on 264 members of 26 Utah Genetic Reference pedigrees. Using segregation analysis, suggestive evidence of linkage for the FEV1/FVC ratio was found on chromosome 2 (heterogeneity lod, 2.36) and chromosome 5 (heterogeneity lod, 2.23). The linkage was also detected by nonparametric variance component linkage analysis. Neither the dominant nor the recessive model could be rejected in the segregation analysis. Neither FEV1 nor FVC had nonparametric logarithm of the odds scores over 1.5. The authors con-

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clude that genetic factors contribute to the inheritance of the FEV1/FVC ratio. Preoperative

In a prospective cohort of 272 consecutive patients evaluated before nonthoracic surgery, McAlister and coworkers (75) identified predictors of increased risk. Postoperative complications occurred in 22 (8%) patients. Predictors of pulmonary complications included Pco2 of 45 mm Hg or higher (odds ratio, 61.0), FVC of less than 1.5 liter (odds ratio, 11.1), maximum laryngeal height of 4 cm or less (odds ratio, 6.9), smoking history of 40 pack-years or more (odds ration, 5.7), and body mass index of 30 or more (odds ratio, 4.1). On multiple regression, three clinical factors were independent predictors of pulmonary complications: age of 65 years or more (odds ratio, 1.8), smoking history of 40 pack-years or more (odds ratio, 1.9), and maximum laryngeal height of 4 cm or less (odds ratio, 2.0). The authors conclude that pulmonary function and clinical assessment identify factors that predict a greater likelihood of pulmonary complications after nonthoracic surgery. In Diabetes Mellitus

The relationship between diabetes and impaired pulmonary function has been inconsistent. To better define the relationship, Walter and coworkers (76) analyzed spirometry data for 3,254 members of the Framingham offspring cohort. Diabetes was defined as a fasting blood sugar of at least 126 mg per dl or treatment with pharmacological agents. Among 1,110 never smokers, both a diagnosis of diabetes and fasting blood glucose were associated with lower than predicted levels of pulmonary function. The adverse effect was stronger among ever smokers than among never smokers, suggesting that hyperglycemia interacts with smoking. The authors conclude that decreased lung function is associated with diabetes and hyperglycemia and that the effect is greater in smokers than in nonsmokers. In Thalassemia

Patients with thalassemia major commonly exhibit abnormal lung mechanics, but the precise nature is poorly described. To address this issue, Carnelli and coworkers (77) measured pulmonary function in 82 transfusion-dependent patients with thalassemia major who were being treated with chelation therapy (desferrioxamine or deferiprone). Patients had a restrictive pattern: 22% decrease in predicted FVC, 20% decrease in predicted FEV1, 23% decreased in predicted peak expiratory flow, and a normal FEV1/FVC ratio. Both FVC and FEV1 were negatively correlated with transfusional iron burden. Diffusing capacity was decreased (even after correction for anemia) and negatively correlated with iron burden and iron overload (as reflected by serum ferritin). Despite the increase in lung capillary blood volume associated with anemia, blood-diffusing capacity was reduced; increased capillary blood volume, however, was sufficient to normalize blood-diffusing capacity when hemoglobin was only partially restored by transfusion. Diffusing capacity of the alveolar–capillary membrane was decreased and negatively correlated with age and serum ferritin. The authors conclude that patients with the thalassemia major have restrictive disease and low diffusing capacity, primarily because of an increase in the thickness of the alveolar–capillary membrane. Physical Fitness

Pelkonen and coworkers (78) investigated the influence of physical activity on the decline in pulmonary function among middleaged men living in rural Finland. Complete follow-up data were available for 429 men for 10 years, 275 men for 20 years, and

186 men for 25 years. Over the first 10 years, men in the highest tertile of physical activity expressed less of a decline in FEV1 (9.8 ml per year) than did men in the lowest tertile. A similar pattern was observed for follow-up periods of 20 and 25 years. A continued high level of physical activity was associated with lower mortality. The authors conclude that a high level of physical activity is associated with a lower rate of decline of pulmonary function in middle-aged and older men. Bronchoscopy

Up to half of patients with histologically normal lymph nodes have micrometastases detected by molecular techniques. To determine whether the expression of human telomerase reverse transcriptase (found by the reverse transcription-polymerase chain reaction) could detect micrometastatic disease, Wallace and coworkers (79) did fine-needle aspiration of lymph nodes (under endoscopic ultrasound) in 39 patients with non–small cell lung cancer and 12 control subjects (being evaluated for benign pancreatic or biliary disease). Human telomerase reverse transcriptase was expressed in 10 of 16 pathologically positive lymph nodes, 18 of 57 pathologically negative lymph nodes from patients with cancer, and 0 of 14 negative nodes from control subjects. Of 18 patients without pathologic evidence of mediastinal disease, 5 (28%) expressed telomerase in at least one lymph node (the clinical significance of this observation is not known). The authors conclude that ultrasound-guided fine-needle aspiration combined with molecular detection of telomerase expression can detect cancer-specific messenger RNA in lymph nodes. An editorial commentary by Massion and Carbone (80) accompanies this article. Staging of patients with lung cancer is undertaken to minimize futile thoracotomies and yet not deny possible curative surgery. To assess the usefulness of endoscopic ultrasound with fineneedle aspiration under conscious sedation in providing tissue proof of inoperability in a single staging test, Fritscher-Ravens and coworkers (81) studied a consecutive cohort of 79 potentially operable patients with suspected or proven lung cancer. Thirtynine patients were found inoperable. Sensitivities of three diagnostic procedures were: endoscopic ultrasound, 63%; computed tomography, 43%; and positron emission tomography, 68%. Specificities were: endoscopic ultrasound, 100%; computed tomography, 91%: and positron emission tomography, 72%. The costs were: computed tomography alone, $549; computed tomography plus positron emission tomography, $2,799; and endoscopic ultra-fine needle aspiration plus computed tomography, $1,695. The authors conclude that the superior specificity and relatively low costs of endoscopic ultrasound combined with fine-needle aspiration make it a valuable method for identifying patients with inoperable lung cancer. An editorial commentary by Kern (82) accompanies this article. Studies of hypervascularity of the bronchial wall in the airway remodeling of asthma have been confined to biopsy specimens. To investigate subepithelial vessels in a less invasive manner, Tanaka and coworkers (83) used a novel, high-magnification bronchovideoscope in 24 patients with stable asthma, 13 patients with COPD, and 12 healthy control subjects. In patients with asthma, the redness of the bronchial mucosa seen on conventional bronchoscopy was found to be caused by a fine vascular network. The density of subepithelial vessels, in terms of both area and length, was greater in patients with asthma than in patients with COPD or in the healthy subjects. The increase in subepithelial vessels was equivalent in 8 steroid-naive and 16 patients with asthma receiving inhaled glucocorticoids. The authors conclude that patients with asthma have increased subepithelial microvessels in the tracheal mucosa and that these vessels are present even in newly diagnosed patients.

Year in Review

Bronchoscopic lung volume reduction achieves collapse of targeted lung regions using a washout solution to disrupt surfactant function and a tissue sealant to prevent reexpansion. Ingenito and coworkers (84) evaluated this procedure in six sheep with papain-induced emphysema. Features of emphysema included 8% increase in total lung capacity, 66% increase in residual volume, and 76% increase in airway resistance. Bronchoscopic lung volume reduction decreased total lung capacity by 16%, decreased residual volume by 55%, and increased vital capacity by 10%. At autopsy, well-organized peripheral scars associated with tissue contraction were observed in 91% of the 36 treated sites. The procedure was tolerated without complications, and there was no evidence of infection, abscess, granuloma formation, or allergic reaction. The authors conclude that bronchoscopic lung volume reduction improved pulmonary function consistently and safely in sheep with experimental emphysema. In a clinical commentary, Culver and colleagues (85) discuss problems related to infection control in the bronchoscopy suite. Conflict of Interest Statement : M.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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