Year in Review Sleep-disordered Breathing, Control of Breathing, Respiratory Muscles, Pulmonary Function Testing, Nitric Oxide, and Bronchoscopy in AJRCCM 2000 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 Epidemiology (4) Risk Factors (3) Pathophysiology Cardiovascular Mechanisms (12) Upper Airway Mechanisms (9) Control of Breathing (2) Circadian Rhythm (1) Clinical Aspects Upper Airway Resistance Syndrome (4) Neuromuscular Disease (1) In Children (2) Diagnostic Techniques (6) Treatment Airway Pressure and Flow (6) Pharmacotherapy (1) Mandibular Devices (2) Surgery (1) Control of Breathing Studies of Animals (3) Pathophysiological Studies of Volunteers (3) Control of Breathing in Clinical Disorders (3) Dyspnea (10) Respiratory Muscles Studies of Animals (6) Pathophysiological Studies of Patients and Volunteers Weight Lifting (1) Exercise (3) Diagnostic Studies (3) Respiratory Muscle Involvement in Clinical Disorders (4) Pulmonary Function Testing Equipment and Techniques (5) Quality Control (2) Normative Values (2) Epidemiology Studies (2) Predicting Postoperative Complications (1) In Heart Failure (1) Closing Volume and Gas Exchange (1) Lung Sounds (1)
Supported by a Merit Review grant from the Veterans Affairs Research. Correspondence and requests for reprints should be addressed to Martin J. Tobin, M.D., Division of Pulmonary and Critical Care Medicine, Room 438E, Building 1, Hines Veterans Affairs Hospital, 5th Avenue & Roosevelt Road, Hines, IL 60141. E-mail:
[email protected] Am J Respir Crit Care Med Vol 164. pp 1362–1375, 2001 DOI: 10.1164/rccm2108124 Internet address: www.atsjournals.org
Nitric Oxide (4) Bronchoscopy (5)
SLEEP-DISORDERED BREATHING Epidemiology
To determine whether snoring is independently associated with sleepiness or is simply a marker of sleep apnea, Gottlieb and coworkers (1) performed a cross-sectional cohort study of 5,777 individuals in the Sleep Heart Health Study. A progressive increase in sleepiness, quantified with the Epworth Sleepiness Scale, occurred across five categories of snoring frequency, ranging from six in nonsnorers to nine in people who snore every night. Excessive daytime sleepiness, defined as greater than 11 on the Epworth scale, increased from 15% in never-snorers to 39% in people who snore every night. After adjusting for the apnea–hypopnea index, a significant relationship between snoring and sleepiness persisted. The authors conclude that snoring is independently associated with sleepiness. In 830 patients with sleep apnea, O’Connor and coworkers (2) investigated the influence of gender on polysomnographic findings. Men had a higher apnea–hypopnea index than women (32 and 20), and severe sleep apnea was eight times commoner in men. Apneas clustered more during rapid eye movement (REM) sleep in women than in men. Apneas that occurred predominantly in the supine position were almost restricted to men. The authors conclude that women have less severe sleep apnea during non-REM sleep than men, whereas they have greater clustering of respiratory events during REM sleep. Findley and coworkers (3) assessed the effect of nasal continuous positive airway pressure (CPAP) on the rate of automobile crashes. Of 50 consecutive patients with sleep apnea, 36 (72%) reported regular use of CPAP over the preceding two years, whereas the remainder did not. Patients using CPAP had fewer crashes than before treatment (0 versus 0.07 crashes per driver per year), whereas the rate of crashes remained high in patients not using CPAP. Of patients involved in crashes, only one-third of the crashes were reported. The authors conclude that CPAP decreases the number of automobile crashes in patients with sleep apnea. To determine the prevalence of habitual sleepiness while driving, Masa and coworkers (4) conducted telephone interviews of randomly selected Spanish drivers. Of 4,002 drivers, 3.6% reported habitual sleepiness when driving, and these individuals had 13 times more automobile crashes than control subjects. Among 90 sleepy drivers who underwent polysomnography, a respiratory event index (based on apneas, hypopneas, and arousals) was higher in those who had automobile crashes. The authors conclude that questioning patients about
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sleepiness while driving, rather than overall sleepiness, may better predict those patients who are likely to have crashes. Risk Factors
To determine whether abnormal oropharyngeal findings on physical examination serve as risk factors for sleep apnea, Schellenberg (5) analyzed data from 420 individuals presenting to a sleep center. Controlling for body weight and neck circumference, multiple logistic regression revealed that enlargement of the lateral wall of the pharynx and enlargement of the tongue were the only significant predictors for sleep apnea (defined as a respiratory disturbance index of at least 15 per hour). The authors conclude that finding enlarged oropharyngeal soft tissues on physical examination increases the likelihood of sleep apnea. Parra and coworkers (6) investigated breathing abnormalities during sleep in 161 patients experiencing a first stroke or transient ischemic attack. Over the first 2–3 days, 71% of patients had an apnea–hypopnea index of at least 10, and 28% had an index exceeding 30; Cheyne–Stokes breathing was present in 26%. Of 86 patients studied at 3 months, 62% had an apnea– hypopnea index of at least 10, and 20% had an index greater than 30; Cheyne–Stokes breathing occurred in 7%. The presence and type of breathing abnormality were not related to the location of the neurological lesion. The authors conclude that breathing abnormalities are common during sleep in patients with their first stroke, but they are not related to the location of the neurological lesion. Because snoring is common in pregnancy, Edwards and coworkers (7) asked, “Does upper airway narrowing contribute to the nighttime increase in blood pressure in women with preeclampsia?” All of 11 women with preeclampsia had partial obstruction of the upper airway during sleep, and this could be eliminated by 6 cm H2O of nasal CPAP. Nighttime blood pressure fell from 146⁄92 mm Hg without treatment to 128⁄73 mm Hg with CPAP. The authors conclude that upper airway obstruction in women with preeclampsia is associated with hypertension that reverses with use of CPAP. Pathophysiology
Cardiovascular mechanisms. Because arousals produce transient increases in blood pressure, Morrell and coworkers (8) assessed whether sleep fragmentation (defined as the number of awakenings and shifts to Stage I sleep as a function of sleep time) would cause blood pressure to increase during wakefulness. Among 1,021 participants in the Wisconsin Sleep Cohort Study, sleep fragmentation in people with an apnea–hypopnea index of less than 1 was associated with higher systolic pressures. An increase in sleep fragmentation of 2 standard deviations was associated with a rise in systolic pressure of 3 mm Hg. In people with an apnea–hypopnea of more than 1, sleep fragmentation and blood pressure were not associated. The authors conclude that in adults without discernible sleep apnea the amount of fragmented sleep is independently associated with higher levels of systolic blood pressure during wakefulness. Peker and coworkers (9) performed a five-year prospective study of mortality in patients admitted to an intensive care unit because of coronary artery disease. Death from cardiovascular disease occurred in 38% of 16 patients with sleep apnea (respiratory disturbance index exceeding 10 per hour), contrasted with 9% of 43 patients without sleep apnea. On multiple regression, the respiratory disturbance index proved an independent predictor of cardiovascular mortality. The authors conclude that untreated sleep apnea is associated with increased mortality from cardiovascular disease in patients with coronary artery disease.
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In patients with an ischemic stroke, Wessendorf and coworkers (10) examined the relationship between plasma fibrinogen and degree of sleep apnea. Of 113 patients, 39% had mild sleep apnea (respiratory disturbance index less than 20) and 24% had moderate sleep apnea (index above 20). The level of fibrinogen was correlated with respiratory disturbance index (r 0.24), duration of longest apnea (r 0.18), and lowest oxygen saturation (r 0.41). The authors conclude that the relationship between fibrinogen and severity of sleep apnea suggests a possible mechanism for the increased risk of stroke in patients with sleep apnea. An editorial commentary by Shamsuzzaman and Somers (11) accompanies this article. Because sympathetic activity is thought to be increased in sleep apnea and because increased sympathetic activity leads to downregulation of adrenergic receptors, Grote and coworkers (12) measured forearm vascular resistance in 10 patients with sleep apnea and 10 control subjects. The vasoconstriction resulting from intraarterial infusion of norepinephrine, an -receptor agonist, was decreased to about half normal in the patients. The vasodilation achieved by isoproterenol, a -receptor agonist, was decreased by 19% in the patients. The decrease in vascular resistance achieved by phentolamine, an -receptor blocker, was the same in the two groups. The authors conclude that the decreased vascular responsiveness to - and -receptor stimulation suggests downregulation of these receptors in patients with sleep apnea. In 40 patients with sleep apnea and hypertension, Kraiczi and coworkers (13) compared the antihypertensive effect of atenolol (1-selective blocker), amlodipine (calcium channel blocker), enalapril (angiotensin-converting enzyme inhibitor), hydrochlorothiazide (diuretic), and losartan (angiotensin receptor antagonist). Atenolol achieved a greater decrease in diastolic blood pressure than the other agents. No agent influenced sleep-disordered breathing. The authors conclude that the data support the notion that overactivity of the sympathetic nervous system contributes to the hypertension of sleep apnea. An editorial commentary by Samet and coworkers (14) accompanies this article. Because sleep apnea is associated with hypertension and because arterial pressure is related to venodilation, Duchna and coworkers (15) investigated the vascular responsiveness of the veins of patients with obstructive sleep apnea. Bradykinin achieved about one-third less dilation of the dorsal hand veins in patients with sleep apnea than in control subjects. The venodilatory response to nitroglycerin also tended to be less in patients, but not significantly so. After 60 days of nasal CPAP, six patients showed a twofold increase in the venodilatory response to bradykinin. The authors conclude that patients with sleep apnea have a blunted venodilatory response to bradykinin and it reverses with CPAP. The mechanism for the coupling of hypertension with sleep apnea is not known. To determine whether the respiratory disorder is secondary to a cardiovascular derangement or it represents a genetically determined phenotype, Carley and coworkers (16) studied three groups of rats: genetically and phenotypically normotensive, genetically and phenotypically hypertensive, and genetically hypertensive but phenotypically normotensive. During non-REM sleep, the two groups carrying hypertension genes had 15 times more apneas than the genetically normotensive group. The authors conclude that the occurrence of sleep apnea in rats that are normotensive but carry a hypertension gene indicates that the respiratory disturbance is a genetically determined phenotype and not secondary to cardiovascular derangement. To determine whether the increases in blood pressure are caused by the arousals alone or by the associated changes in
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ventilation, Trinder and coworkers (17) studied eight patients with Cheyne–Stokes respiration. During wakefulness (when there are no arousals), systolic blood pressure fluctuated by 11 mm Hg and the fluctuations were in synchrony with the apnea–hyperpnea cycle. During sleep, arousals occurred at the end of an apnea; fluctuations in systolic pressure were similar to wakefulness, and increases in pressure were related to the increases in ventilation (r 0.70). The authors conclude that the fluctuations in blood pressure in patients with Cheyne–Stokes respiration are primarily caused by fluctuations in ventilation. To determine whether release of free oxygen radicals might be a mechanism contributing to the link between sleep apnea and cardiovascular disease, Schulz and coworkers (18) measured superoxide release in 18 patients with sleep apnea. Release of superoxide from the patient neutrophils was determined ex vivo by challenging the neutrophils with bacterial tripeptide formylmethionylleucylphenyalanine and the calcium ionophor, A23; measurement of superoxide dismutaseinhibitable reduction of cytochrome c indicated the production of superoxide. Superoxide production was increased in the patients, and treatment with nasal CPAP produced a rapid and persistent decrease in its production. The authors conclude that patients with sleep apnea have a markedly increased release of superoxide from circulating neutrophils that is reversed by two nights of CPAP. Because of the link between sleep apnea and cardiovascular disease, Ip and coworkers (19) asked, “Do patients with sleep apnea have an abnormality in circulating nitric oxide?” In 30 men with sleep apnea (apnea–hypopnea index, 48), serum nitric oxide (the sum of nitrite and nitrate metabolites) was 38% lower than in healthy control subjects. Serum nitric oxide was correlated with apnea–hypopnea index (r 0.39), oxygen desaturation time (r 0.35), and systolic blood pressure (r 0.34). One night of nasal CPAP produced a 2.7fold increase in serum nitric oxide in 22 patients. The authors conclude that the data suggest a role for nitric oxide as a mediator of the cardiovascular abnormalities in patients with sleep apnea. Upper airway mechanisms. Because both collapsibility of the pharynx and abnormality of craniofacial structures are thought to contribute to obstructive sleep apnea, Sforza and coworkers (20) examined the relationship of one to the other. Recordings of pressure and flow were used to calculate pharyngeal collapsibility in 57 patients who had an apnea–hypopnea index of 73. Pharyngeal critical pressure for collapsibility was related to the length of the soft palate, the distance between the hyoid bone and the posterior pharynx, and the distance between the hyoid and the posterior nasal space. The authors conclude that both abnormal soft tissue of the pharynx and a low position of the hyoid body contribute to collapsibility of the upper airway. King and coworkers (21) studied 12 healthy subjects to determine whether upper airway obstruction causes sleep apnea. A decrease in nasal pressure to 10 cm H2O caused 33 apneas per hour, accompanied by oxygen desaturation, arousals, and disruption of sleep stages. On a second night, the abnormalities were reproducible. After the second night, daytime sleep latency fell from 7 to 3 minutes. The authors conclude that a decrease in pharyngeal pressure is sufficient to cause sleep apnea. Because increased activity of the pharyngeal dilator muscles is important for maintaining airway patency in patients with sleep apnea, Malhotra and coworkers (22) investigated mechanisms contributing to this compensatory activity. When five patients with a tracheostomy breathed through the nose (which exposes the pharynx to negative pressure), they developed greater increases in phasic and tonic activity of the ge-
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nioglossus than when breathing through the tracheal stoma (which should not stimulate the pharynx). The authors conclude that upper airway stimuli help mediate the increased activity of the pharyngeal dilators. To investigate the stimulatory action of mechanoreceptors on pharyngeal dilator muscles, Malhotra and coworkers (23) obtained electromyograms of two dilator muscles: the genioglossus (which is phasically active on inspiration) and the tensor palatini (which is tonically active). Studies were performed in 15 healthy subjects during wakefulness and non-REM sleep; to lower the pressure in the upper airway, the subjects intermittently inspired through a resistor. Activity of the genioglossus was strongly correlated with upper airway pressure during wakefulness, but less so during non-REM sleep. Activity of the tensor palatini was not correlated with any stimulus. The authors conclude that pharyngeal pressure modulates genioglossal activity during wakefulness, and has less effect during sleep. Because sleep apnea is 2–10 times commoner in men, Pillar and coworkers (24) asked, “Do men and women differ in their response to inspiratory resistive loading during non-REM sleep?” A resistance of 25 cm H2O per liter per second produced a 69% greater fall in tidal volume in men than in women. The increase in pharyngeal resistance with resistive loading was six times greater in men than in women. Both achieved the same minute ventilation with loading, indicating no differences in respiratory drive. Differences in activity of pharyngeal muscles, genioglossus, and tensor palatini did not explain the response. The authors conclude that men are more vulnerable to load-induced hypoventilation than women, secondary to increased collapse of the upper airway. An editorial commentary by O’Donnell and coworkers (25) accompanies this article. In 18 healthy awake subjects, Shea and coworkers (26) investigated the response of genioglossal muscle activity to changes in arterial blood gases typically seen in patients with mild sleep apnea (increases and decreases in end-tidal PCO2 of 5 torr and falls in oxygen saturation to 87%). The changes produced doubling of minute ventilation. Phasic activity of the genioglossus increased by 70% among differing conditions (r 0.97). The response of the genioglossus to the introduction of negative pressure in the upper airway (13 cm H2O) was not altered by the conditions. The authors conclude that changes in genioglossal activity can be fully explained by the action of mechanoreceptors and that chemoreceptor inputs are minimal. Because sleep apnea and external stimulation of the phrenic nerves are both associated with the combination of upper airway collapse and continued activity of the diaphragm, Series and coworkers (27) assessed the worth of magnetic stimulation of the phrenic nerves as a tool for probing mechanisms of sleep apnea. In eight awake patients with sleep apnea, phrenic nerve stimulation produced an increase in transdiaphragmatic pressure that was accompanied by a pattern of inspiratory flow limitation. Use of nasal CPAP caused the pattern of flow limitation to decrease from 78 to 18%. The authors conclude that magnetic stimulation is a useful tool for evaluating the dynamics of flow through the passive upper airway in patients with sleep apnea. To understand the respiratory manifestations of central sleep apnea, Solin and coworkers (28) measured the central CO2 response (increase in ventilation during CO2 rebreathing) and the peripheral CO2 response (ventilatory response to a single inhalation of CO2) in 32 patients with congestive heart failure (12 with central sleep apnea, 8 with obstructive sleep apnea, and 12 without apneas), 11 patients with idiopathic central sleep apnea (no heart failure), and 8 healthy subjects.
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Both the central and the peripheral CO2 ventilatory responses were about twice as high in the two groups with central sleep apnea (heart failure or idiopathic) than in the other groups. Among all patients with heart failure, the central apnea–hypopnea index was correlated with the peripheral CO2 ventilatory response (r 0.63), but not with the central CO2 ventilatory response; the waking PCO2 was correlated with the central response (r 0.61). The authors conclude that increased central responsiveness predisposes patients with heart failure to central sleep apnea by promoting hypocapnia and exposing the apnea threshold to fluctuations in ventilation, whereas the increased peripheral responsiveness determines the severity and periodicity of central sleep apneas. Control of breathing. Because of methodological concerns with previous reports that sleep deprivation causes a decrease in the ventilatory response to hypercapnia, Spengler and Shea (29) reexamined this issue while strictly controlling behavioral and environmental conditions. In 10 subjects, measurements were repeated every two hours over a 41-hour period, making it possible to examine the effects of 24 hours of sleep deprivation. Sleep deprivation had no effect on the ventilatory response to hypercapnia or on the metabolic rate. The authors conclude that uncontrolled activities or environmental influences may have confounded the data in earlier reports. To see whether hypercapnia alone could induce arousal in the absence of afferent signals from the mechanoreceptors, Ayas and coworkers (30) did polysomnograms in four patients with cord lesions above C3. Patients with such lesions are not able to alter pleural pressure or the tension within their respiratory muscles. During non-REM sleep, increases in inspired CO2 invariably induced arousal within five minutes (mean time to arousal, 115 seconds) and each patient awoke and complained of dyspnea. Arousals occurred when end-tidal PCO2 increased by a mean of 16 mm Hg. The authors conclude that slow and rapid increases in PCO2 can induce arousals in humans in the absence of changes in mechanoreceptor activity. Circadian rhythm. The diurnal variation in pulmonary function may reflect an endogenous circadian rhythm or be caused by diurnal variations in behavior or of the environment. To address this issue, Spengler and Shea (31) measured several variables every two hours in 10 healthy subjects who remained awake for 41 hours in a controlled constant environment. Aligning data to the minimum core temperature, cosinor analysis revealed significant circadian variation in FEV1, cortisol, and core temperature, but not in forced vital capacity or peak flow rate. The peak-to-trough ranges were 2–3% of the mesor. The circadian minima always occurred during the usual time of sleep (although the subjects were awake). Sleep deprivation had no effect on any variable. The authors conclude that circadian rhythms contribute to diurnal variations in pulmonary function. Clinical Aspects
Upper airway resistance syndrome. To determine the frequency of episodes of upper airway narrowing and arousal in patients with the upper airway resistance syndrome, Rees and coworkers (32) studied eight patients with the syndrome and eight healthy control subjects. Episodes of increased upper airway resistance were equally frequent in the two groups. At the end of an episode, the patients had more negative esophageal pressure than the control subjects (15 and 11 cm H2O) and more cortical arousals (10 and 3 per hour slept). The authors conclude that episodes of upper airway narrowing occur in patients with the upper airway resistance syndrome and also in healthy subjects, but inspiratory efforts are greater and arousals more common in the patients.
The polysomnographic features of the upper airway resistance syndrome are a progressive increase in esophageal pressure terminated by an arousal, followed by an abrupt decrease in esophageal pressure. Because some patients display an abrupt decrease in esophageal pressure without an arousal, Black and coworkers (33) did spectral analysis on EEG data, looking for changes invisible to the naked eye. Abrupt decreases in esophageal pressure were accompanied by increases in delta band activity, regardless of whether arousals occurred. The abrupt decreases in esophageal pressure were greater and longer lasting when accompanied by an arousal. The authors conclude that increased swings in esophageal pressure are accompanied by substantial alterations in the electroencephalogram, even if conventional criteria for arousal are not met. The distinctiveness of upper airway resistance syndrome as a diagnostic entity is debated by Guilleminault and Chowdhuri (34) and Douglas (35), with rebuttals from each (36, 37). Neuromuscular disease. Because amyotrophic lateral sclerosis can cause severe dysfunction of the diaphragm and because the diaphragm is the only inspiratory muscle active during REM sleep, Arnulf and coworkers (38) did polysomnography in 21 patients with amyotrophic lateral sclerosis. Diaphragmatic function was normal in 8 patients and abnormal in 13. REM sleep was shortened (7% of sleep time) in patients with abnormal diaphragms, and normal (18% of sleep time) in patients without diaphragmatic dysfunction. Apneas and hypopneas were rare in both groups. Survival was shorter in patients with diaphragmatic dysfunction (217 days) than in those with normal function (619 days). The authors conclude that diaphragmatic dysfunction in patients with amyotrophic lateral sclerosis causes a dramatic decrease in the duration of REM sleep, with associated decrease in survival. In children. In 20 children with sleep apnea and 10 healthy control subjects, Goh and coworkers (39) found that the distribution of sleep stages in the patients did not differ from the control subjects. Of obstructive apneas, 55% occurred during REM sleep; apnea index, apnea duration, and desaturation were greater during REM than non-REM sleep. The number of apneas, irrespective of association with REM, more than doubled between the first and final third of the night. The authors conclude that children with sleep apnea have normal sleep architecture, and that apneas occur predominantly during REM sleep and worsen over the course of the night. Berger and coworkers (40) reported an infant presenting with recurrent apnea and cyanosis, in whom oxygen exacerbated the instability of periodic breathing. While breathing oxygen, periods of breathing lasting 60 to 90 seconds alternated with apneas lasting up to 60 seconds. When oxygen was discontinued, the infant developed more profound desaturation than was present before oxygen therapy. The authors conclude that oxygen therapy involves potential risks when used to treat infants with unstable breathing patterns. Diagnostic Techniques
The lack of a standardized methodology for identifying hypopneas and the lack of an agreed-on definition for the respiratory disturbance index contributes to conflicting estimates of the severity of sleep disordered breathing. To shed light on this problem, Redline and coworkers (41) compared 10 respiratory disturbance indexes calculated according to different criteria. Data were taken from unattented 12-channel recordings performed overnight in 5,046 participants in the Sleep Heart Health Study. There was a 10-fold variation among the median value of the 10 respiratory disturbance indexes (ranging from 29 when the index was based solely on flow or volume criteria to 2 when the index also required 5% desaturation).
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The authors conclude that correlation between respiratory disturbance indexes is highest when criteria included measures of both apnea–hypopneas and oxygen desaturation. Zerah-Lancner and coworkers (42) asked whether pulmonary function testing could identify patients with sleep apnea. In an initial group of 168 snorers with suspected sleep apnea, specific conductance and daytime oxygen saturation were important components in a logistic regression model for predicting sleep apnea. The model was then prospectively tested in 101 snorers: sensitivity was 100% and specificity was 84%. A negative predictive value of 100% suggests that the model can identify which snorers have a low likelihood of sleep apnea, rendering polysomnography unnecessary in that subgroup. The authors conclude that a statistical model based on pulmonary function tests is effective in excluding sleep apnea in suspected patients. In 103 patients evaluated for sleep apnea, Portier and coworkers (43) compared polysomnography done with a portable home system with that in a sleep laboratory. Disruption of sleep stages was similar with the two systems. In 36% of patients, the two systems differed in the calculation of the respiratory disturbance index by more than 10. The discrepancy was greatest in patients with severe disease, and arose from the poor quality of the flow signal in the home system. The authors conclude that polysomnography using a portable home system is not reliable in all patients with sleep apnea. In 422 infants undergoing an overnight sleep study, WeeseMayer and coworkers (44) compared three methods for identifying apneas: an inductance plethysmograph for home use, a nasal end-tidal CO2 sensor, and a thermistor. There were considerable discrepancies between the three methods. Among 87 apneas identified by all three methods, no two methods showed good agreement on apnea duration. The authors conclude that the inductance plethysmograph system offers a means for recording data in the home. Argod and coworkers (45) compared the accuracy of pulse transit time against esophageal pressure for detecting increases in upper airway resistance and hypopnea (but not apnea). Pulse transit is the time a pulse pressure wave takes to travel from the heart (timed as the R wave on the EKG) to the periphery (measured with a finger cuff). Two experienced observers scored 340 nonapneic disturbances on two occasions. Interobserver variability was 37% for pulse transit time and 39% for esophageal pressure. Using esophageal pressure as the reference standard, pulse transit time had a sensitivity of 80% and a positive predictive value of 91%. The authors conclude that pulse transit time can be used as an alternative to esophageal pressure for scoring increases in upper airway resistance and hypopnea. On a multiple sleep latency test, the occurrence of two or more rapid eye movements (REMs) at sleep onset is thought to suggest narcolepsy. Patients with obstructive sleep apnea, however, may also display this abnormality. In 1,145 patients with suspected sleep apnea, Chervin and Aldrich (46) reviewed multiple sleep latency tests, and found that 4.7% had at least two REMs at sleep onset. On logistic regression analysis, four variables predicted the abnormality: male gender, a 5-minute decrease in latency on multiple sleep latency test, a 90-minute decrease in latency to nocturnal REM sleep, and the extent of oxygen desaturation. The authors conclude that when more than two REMs occur unexpectedly at sleep onset, these four variables should be considered before arriving at a diagnosis of narcolepsy. Treatment
Airway pressure and flow. To determine which factors predict improved daytime function with use of nasal CPAP, Kingshott
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and coworkers (47) prospectively assessed daytime function before and after six months of treating 62 patients with sleep apnea. The number of microarousals and apnea–hypopnea index were poor predictors of daytime function. The degree of nighttime hypoxemia predicted improvements in symptoms, quality of life, reaction time on cognitive assessment, and sleep latency on maintenance of wakefulness test. Improvement in daytime function was correlated with use of CPAP. The authors conclude that baseline polysomnographic variables are poor predictors of the response to CPAP. To assess whether use of an auto-CPAP machine in the home could be used to determine the pressure setting of CPAP for preventing apneas, Series (48) undertook a one-to-two week trial in 40 patients with a new diagnosis of sleep apnea. After determining the necessary level of pressure, a fixed CPAP machine was set at that level; after 2 weeks of treatment, a sleep study was done. The pressure in the fixed machine had to be increased by 1 cm H2O over the pressure estimated from the auto-CPAP machine. The authors conclude that auto-CPAP provides a new and reliable way of identifying appropriate settings on conventional CPAP machines outside of the hospital setting. Although nocturnal CPAP is used in patients with congestive heart failure and central sleep apnea, its effects on the cardiac volumes of patients with congestive heart failure has not been studied. Mehta and coworkers (49) addressed this issue in 13 patients with ischemic cardiomyopathy and 9 patients with idiopathic dilated cardiomyopathy. CPAP did not affect ventricular volumes in patients with ischemic cardiomyopathy, but caused global reductions in patients with idiopathic dilated cardiomyopathy. In patients with dilated cardiomyopathy, the decreases in end-systolic and end-diastolic volumes were greater for the right ventricle than for the left ventricle. The authors conclude that CPAP causes greater reductions in ventricular volume in patients with dilated cardiomyopathy, presumably because they have more compliant ventricles, and it causes greater reductions of the right than of the left ventricle, presumably because the wall is thinner. Schneider and coworkers (50) investigated the effect of transtracheal insufflation of air in five patients with sleep apnea who were breathing through a closed tracheostomy. Low gas flow had little effect, but insufflations of 10–15 liter per minute halved the breathing disturbances during non-REM sleep. Because high flows also caused intermittent laryngeal obstruction, the system was adjusted to switch off the delivery of flow during an obstruction. The modified system achieved a 6-fold decrease in respiratory disturbances and arousals during non-REM sleep. The authors conclude that insufflating gas into the trachea at high flows decreases sleep apnea. The efficacy of nasal CPAP in the treatment of obstructive sleep apnea is debated by Davies and Stradling (51) and Wright and Sheldon (52), with rebuttals from each (53, 54). Pharmacotherapy. In 11 healthy subjects, Sunderram and coworkers (55) did a double-blind crossover study of the effect of a selective inhibitor of serotonin uptake, paroxetine hydrochloride, on the activity of the genioglossus. Five days of treatment with the inhibitor produced increases in surface electrode recordings of the genioglossal electromyogram, and the increased activity persisted with application of CPAP or when the subjects were challenged with hypercapnia. The authors conclude that the results suggest that paroxetine has a central serotonergic action. Mandibular devices. In 28 patients with untreated sleep apnea, Henke and coworkers (56) evaluated a new oral device for advancing the mandible and also determined whether success depended on the site of airway closure. The device consisted of plastic trays molded to the teeth with an elastic strap
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pulling the mandible forward. Apnea–hypopnea index decreased from 53 to 21, and 68% of the patients experienced a decrease of at least 50%. All three patients with closure of the lower pharynx during sleep had a greater than 80% fall in apnea– hypopnea index, and similar improvement occurred in two of nine patients with closure in the velopharynx. The authors conclude that this oral device is successful, and that severity of disease or location of airway closure should not be used to deny treatment. In 24 patients with sleep apnea, Bloch and coworkers (57) did a randomized crossover comparison of two appliances for advancing the mandible: a two-piece appliance used by other investigators, and a new single-piece appliance considered to be simpler and more robust. The apnea–hypopnea index was 23 at baseline, and it decreased to 9 with one week of treatment using either device. Both devices caused a decrease in daytime sleepiness. More patients preferred the one-piece device. The authors conclude that both mandibular devices are effective in alleviating sleep apnea. Surgery. In patients with suspected collapse of the hypopharynx, Bettega and coworkers (58) evaluated the benefit of a two-step approach to maxillofacial surgery. A limited mandibular osteotomy (with or without uvulopalatopharyngoplasty) was performed in 44 patients, but achieved no improvement in apnea–hypopnea index. A full maxillomandibular advancement osteotomy was performed in 20 patients (13 had undergone the previous procedure), and it decreased the apnea–hypopnea index from 59 to 11. The authors conclude that limited mandibular osteotomy is ineffective in most patients with sleep apnea, whereas a full maxillomandibular advancement procedure is effective.
CONTROL OF BREATHING Studies of Animals
In rats, Czapla and coworkers (59) studied the cardiorespiratory effects of the -opioid receptor agonists, endomorphin 1 and 2, and an enkephalin-derived peptide, DAMGO. The threshold dose for analgesia was similar for the three agents. All three compounds produced biphasic changes in minute ventilation: a decrease for 4–6 seconds, followed by an increase for 10–12 minutes. Morphine produced a decrease in ventilation without a subsequent rise. Endomorphin 2 and DAMGO decreased heart rate and blood pressure, whereas endomorphin 1 decreased heart rate but not blood pressure. The authors conclude that the analgesic, respiratory, and cardiovascular actions of -opioid receptor agonists can be dissociated, and that compounds related to endomorphin 1 could yield analgesics of improved safety. To assess the influence of endogenous opioids on respiration, Lee and coworkers (60) administered naloxone hydrochloride, an opioid antagonist that crosses the blood–brain barrier, to 6-week-old obese Zucker rats (a genetic model of morbid obesity). The rats developed decreases in resting minute ventilation, ventilatory response to hypercapnia, and peak oxygen consumption. The antagonist had no effect on 16-week-old rats or on lean rats. Naloxone methiodine, an opioid antagonist that does not cross the blood–brain barrier, had no effect on any of the groups. The authors conclude that endogenous opioids modulate the central respiratory controller of young obese rats, and the modulation disappears by 16 weeks of age. Because N-methyl-D-aspartate (NMDA) glutamate receptors play a critical role in hypoxic chemosensitivity, Ohtake and coworkers (61) investigated their development by measuring ventilation in rats. An antagonist of the NMDA glutamate receptor, MK-801, increased minute ventilation in 15-day-old
rats; the ventilatory response to hypercapnia was not changed. The antagonist had no effect on 5- and 10-day-old rats. Immunostaining for NMDA receptor subunit NR1 and c-Fos revealed increased expression of NR1 in the nucleus tractus solitarii with advancing age; expression of c-Fos was increased by hypoxia. The authors conclude that expression of the NMDA glutamate receptor in the brainstem undergoes postnatal maturation, which closely parallels the development of the hypoxic ventilatory response. Pathophysiological Studies of Volunteers
Peripheral chemoreceptor function is assessed in infants by measuring the percentage decrease in minute ventilation while inspiring 100% for 30 seconds. In 18 infants, Bouferrache and coworkers (62) compared the standard method, based on the change in mean ventilation, with a new approach, based on calculating the time to the first significant change in ventilation after commencing hyperoxia. The new method yielded greater decreases in minute ventilation and tidal volume than the old approach; reproducibility was also better. The authors conclude that a time-based approach to quantifying the ventilatory response to hyperoxia improves assessment of peripheral chemoreceptor function. Hypoxia causes periodic breathing in the presence of sleep or hypocapnia. To determine the effect of hypoxia on variability of breathing in awake normocapic subjects, Jubran and Tobin (63) lowered oxygen saturation from 98 to 79% in 14 healthy subjects. Hypoxia increased the overall variability of every breath component, and decreased the strength of the relationship for expiratory time between one breath and the next. The increased variability of breathing with hypoxia resulted from increases in both random and oscillatory elements. The authors conclude that hypoxia induces ventilatory oscillations even in the absence of hypocapnia and sleep, suggesting that neural responses may have a more important role in the genesis of hypoxia-induced oscillations than previously recognized. Because swallowing and breathing need to be carefully coordinated to avoid aspiration, Kijima and coworkers (64) investigated the influence of changes in lung volume on the swallowing reflex in 11 healthy subjects. Increases in lung volume, achieved by negative pressure applied to the thorax, decreased the number of swallows during continuous infusion of water; the latency of swallowing (time from delivering a bolus of water into the pharynx to the onset of activity on a submental electromyogram) was also increased. The normal coupling of swallowing with expiration was lost. The authors conclude that increased lung volume inhibits the swallowing reflex and prevents its coupling with expiration. Control of Breathing in Clinical Disorders
To see whether passive movement of the feet would increase alveolar ventilation in children with congenital central hypoventilation syndrome, Gozal and Simakajornboon (65) studied six patients during non-REM sleep. The feet were moved at the ankles, either manually or with a motor achieving 40–50 strokes per minute. In 74 trials not associated with change in sleep state, motion decreased end-tidal PCO2 from 59 to 41 torr and increased frequency from 10 to 21 breaths per minute. The authors conclude that the improvement in alveolar ventilation may result from activating mechanoreceptor pathways, rather than by respiratory entrainment. Manning and Leiter (66) reported a young woman with severe central hypoventilation syndrome caused by a medullary glioma located slightly dorsal to and to the right of the midline, a region not generally associated with CO2 chemosensi-
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tivity. The patient had marked central sleep apnea (94 events per hour). While awake, she displayed an irregular breathing pattern with end-tidal CO2 ranging from 5.3 to 10.9%. Her PCO2 fell with voluntary hyperpnea, but not with progesterone or acetazolamide. The patient’s breath-holding time was short and limited by air hunger. The authors conclude that central hypoventilation syndromes may differ in their effects on respiratory control and respiratory sensation. To determine the mechanism of oxygen-induced hypercapnia, Robinson and coworkers (67) employed the multiple inert gas elimination technique in 22 patients with COPD. After breathing 100% oxygen for 20 minutes, 12 patients developed an increase in PCO2 of at least 3 torr (mean, 8.3 torr) and 10 patients developed a decrease of 1 torr. Minute ventilation fell by 1.8 liters per minute in the retainers, but did not change in the nonretainers. The retainers, but not the nonretainers, developed an increase in an index of dead space ventilation, possibly because of bronchodilation, which will increase ventilation to poorly perfused regions and aggravate hypercapnia. The authors conclude that oxygen-induced hypercapnia is mainly due to a fall in minute ventilation and less so to an increase in dead space. Dyspnea
Moy and coworkers (68) asked, “Does the quality of dyspnea differ between the bronchospastic and mechanical load components of mild asthma?” Eight patients described dyspnea according to a 19-item list. Of 26 trials of methacholine bronchoprovocation, “chest tightness” or “constriction” was chosen 92% of the time, whereas they were chosen for only 3% of the 72 trials of breathing through external resistors. The authors conclude that the sensation of chest tightness in mild asthma is distinct from that of effort and it is not related to the imposed mechanical load. In a study of five healthy subjects, Lansing and coworkers (69) asked, “Does dyspnea consist of two qualitatively different sensations, ‘air hunger’ and ‘respiratory work or effort?’” As PCO2 and a target level of voluntary breathing were varied, the subjects rated the two sensations. At constant ventilation, changes in PCO2 produced steeper changes in air hunger. At constant PCO2, changes in ventilation produced steeper changes in ratings of work or effort. The authors conclude that “air hunger” is qualitatively different from “work or effort” and that the sensations arise from different afferent sources. To determine the differing sensations occurring during acute bronchoconstriction, Killian and coworkers (70) studied 232 subjects who inhaled sufficient methacholine to achieve a 20% decrease in FEV1. Ten different expressions were used to describe dyspnea. Five specific symptoms, difficult breathing, chest tightness, breathlessness, labored breathing, and chest pain, accounted for 71% of the variability in the dyspnea experienced during acute bronchoconstriction. Dyspnea was more intense in women and less intense with aging. Chest pain was easily discriminated, whereas difficult and labored breathing was not. The authors conclude that different sensations are elicited by the activation of different receptors by different stimuli during bronchoconstriction. To assess the influence of psychological state on change in dyspnea and ventilation while breathing through small inspiratory loads, Lavietes and coworkers (71) studied healthy control subjects and patients attending a chronic fatigue center. Breathing through resistive loads of 1.34 and 3.54 cm H2O per liter per second over five minutes caused some subjects to become more dyspneic than others. Subjects developing dyspnea scored higher on a scale for mental depression, but their ventilation did not differ from that of the nondyspneic sub-
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jects. The authors conclude that differences in psychologic profile contribute to the degree of discomfort caused by an increase in airway resistance. Because furosemide may inhibit vagal receptors in the airways, Nishino and coworkers (72) undertook a randomized, double-blind trial of the effect of inhaled furosemide on dyspnea in 12 subjects. Furosemide produced about a 50% increase in breath-holding time. When breathing through an inspiratory resistive load combined with hypercapnia, subjects developed less dyspnea, and developed it more slowly, after inhaling furosemide. The authors conclude that inhaled furosemide alleviates dyspnea caused by breath holding and by the combination of resistive loading and hypercapnia. Vibrating the parasternal region of the ribcage decreases dyspnea, possibly through an increase in afferent information from the intercostal muscles. Leduc and coworkers (73) tested this possibility in dogs. During apnea, vibrating the third intercostal space produced prominent activity of the external intercostals; activity was much less in the parasternal intercostals, and occurred only in about half the animals. During spontaneous breathing, vibration during inspiration doubled neural drive to the external intercostals but had no effect on the parasternal intercostals; tidal volume did not change. Vibration during expiration affected neither muscle. The authors conclude that vibration has a greater effect on the external intercostals because they contain more muscle spindles. In rats, Ho and coworkers (74) investigated the action of prostaglandin E2 on vagal C-fiber afferents. Infusion of protaglandin E2 did not alter baseline activity of vagal C-fibers but it markedly enhanced the effect of capsaicin, a potent and selective stimulant of these fibers. Prostaglandin E2 also increased the response of C-fibers to lactic acid, adenosine, and lung inflation, but it did not alter the responses of either slowly adapting or rapidly adapting pulmonary receptors to inflation. The authors speculate that release of prostaglandin E2 may contribute to the dyspnea and airway irritation caused by airway inflammation. An inspiratory effort against an occlusion elicits evoked potentials over the somatosensory cortex, and the first positive peak is thought to indicate afferent information arriving at the cortex. Davenport and coworkers (75) found that an inspiratory occlusion elicited a first peak on evoked potentials in all of 15 healthy children and 14 of 15 children with asthma, but the peak was not found in 6 of 11 children with a high risk for life-threatening asthmatic attacks. The authors conclude that some children with life-threatening asthma have an abnormality in the neural processing of afferent information arising from an inspiratory stimulus. Symptom perception and respiratory sensation in asthma are discussed in the summary of an NHLBI workshop by Banzett and colleagues (76). Campbell (77) recalls a study of the mechanism of dyspnea during elastic loading.
RESPIRATORY MUSCLES Studies of Animals
A point mutation in the dystrophin gene results in a lack of dystrophin, a membrane-associated protein, in patients with Duchenne muscular dystrophy. The same defects occur in the mdx mouse, leading to widespread use of this animal in research on muscle dystrophy. In mdx mice, Attal and coworkers (78) assessed function of the sternohyoid, a dilator that maintains pharyngeal patency. Compared with controls, peak tetanic tension of the sternohyoid of mdx mice was decreased by 50%, maximum velocity of shortening was reduced by
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16%, and peak mechanical power was decreased by 67%. In both groups, the sternohyoid was composed exclusively of fast myosin isoforms; in the mdx mice, composition of myosin heavy chain showed an increase in II-X and a decrease in II-B. The authors conclude that mdx mice offer an excellent model for studying Duchenne muscular dystrophy. The different isoforms of myosin heavy chain determine the fiber type and functional characteristics of a muscle. Gea and coworkers (79) studied the expression of the genes encoding isoforms of myosin heavy chain in the respiratory muscles of dogs. At baseline, mRNA expression for the slow and fast isoforms was similar throughout different regions of the diaphragm. After inspiring through a resistance of 80 cm H2O per liter per second for 2 hours on four consecutive days, expression of mRNA for the slow isoform increased in the costal diaphragm (30%), the crural diaphragm (12%), and the external intercostals (27%); however, expression of mRNA for the fast isoform did not change. The authors conclude that inspiratory loading induces expression of the slow isoform of the myosin heavy chain in respiratory muscles. Because superoxide is released from the contracting diaphragm and because scavengers of superoxide decrease the rate of diaphragmatic fatigue, Stofan and coworkers (80) investigated formation and release of free radicals by the isolated rat diaphragm. Release of superoxide during contraction was measured after blocking two pathways that generate free radicals: blocking cyclooxygenase with indomethacin had no effect, whereas blocking xanthine oxidase with oxypurinol slightly decreased its release. Decreasing muscle length, increasing CO2, and decreasing the frequency of muscle stimulation also blocked the release of superoxide. The authors conclude that common physiologic alterations significantly influence the release of oxygen free radicals by contracting muscles. To determine whether four days of increased airway resistance would damage the diaphragm, Reid and Belcastro (81) used banding to decrease the tracheal lumen of rats by 33%. The animals developed hypoxemia and respiratory acidosis. The diaphragm of the banded rats contained increased amounts of calpain, a thiol protease found in the cytosol that degrades actin and desmin. Histology revealed abnormal muscle in the diaphragm and increase in connective tissue. The authors conclude that an increase in airway resistance causes worsening gas exchange, an increase in calpain, and diaphragmatic injury. In a rat model of septic peritonitis resulting from cecal ligation and perforation, Fujimura and coworkers (82) investigated the effect of a -agonist, isoproterenol, on diaphragmatic contractility. Sixteen hours after injury, a hemidiaphragm was removed and placed in an organ bath. Infusion of isoproterenol improved diaphragmatic contractility and it also accelerated recovery from fatigue (induced by repetitive stimulation of the muscle strip). Isoproterenol produced increased levels of cyclic AMP in the muscle; a derivative of cyclic AMP mimicked the inotropic action of isoproterenol; and a -blocker, propranolol, abolished the effect of isoproterenol. The authors conclude that isoproterenol improves diaphragmatic contractility and accelerates recovery from fatigue in septic peritonitis by activating the adenyl cyclase system. To investigate the effect of oxygen-derived free radicals on diaphragmatic contractility, Fujimura and coworkers (83) used a rat model of septic peritonitis achieved by cecal ligation and perforation. Force–frequency curves performed on a removed hemidiaphragm revealed decreased contractility. Levels of malondialdehyde, an index of lipid peroxidation mediated by oxygen-derived free radicals, were increased in the diaphragm, as were two of the main antioxidant enzymes, superoxide dismutase and glutathione peroxidase. Diaphragmatic contractil-
ity was improved by the administration of polyethylene glycolabsorbed superoxide dismutase (a scavenger of superoxide ions), polyethylene glycol-absorbed catalase (a scavenger of hydrogen peroxide), and dimethyl sulfoxide (a scavenger of hydroxyl radicals) before the cecal injury; these agents also prevented the increase of malondialdehyde in the diaphragm. The authors conclude that several oxygen-derived free radicals contribute to the decreased contractility of the diaphragm in septic peritonitis. Pathophysiological Studies of Patients and Volunteers
Weight lifting. Because weight lifters have greater diaphragmatic mass and can generate greater inspiratory pressures, Al Bilbeisi and McCool (84) measured the change in transdiaphragmatic pressure in six subjects performing biceps curls, bench presses, power lifts, and sit-ups. Transdiaphragmatic pressure increased according to the intensity of the task, reaching up to 65% of maximum. The contribution of gastric pressure to transdiaphragmatic pressure increased from 58% at baseline to 85% during the activities. The authors conclude that recruitment of the diaphragm during weight lifting is sufficient to provide a training stimulus. Exercise. To determine whether high-intensity exercise in COPD would cause diaphragmatic fatigue, Mador and coworkers (85) studied 12 men with COPD of moderate severity (FEV1, 50% of predicted). The patients cycled at 60–70% of maximal capacity to the limit of tolerance (workload of 60 watts performed over 10 minutes). Before exercise, phrenic nerve stimulation produced a twitch transdiaphragmatic pressure of 20 cm H2O. Exercise did not produce a decrease in overall twitch pressure, although two patients had persistent reductions of more than 10%. The authors conclude that high-intensity exercise does not cause diaphragmatic fatigue in most patients with COPD. The development of symptoms during exercise causes many patients with COPD to become sedentary and their limb muscles may become deconditioned. To determine whether highintensity exercise causes fatigue of the quadriceps, Mador and coworkers (86) studied 19 men with COPD (FEV1, 42% of predicted) who cycled at 60–70% of maximal capacity to exhaustion (workload of 54 watts for 10 minutes). When the femoral nerves were stimulated 30 minutes after exercise, twitch force of the quadriceps had fallen by 24%. The authors conclude that heavy exercise causes patients with COPD to develop quadriceps fatigue. To determine whether high-intensity exercise causes fatigue of the diaphragm and quadriceps of healthy elderly subjects, Mador and coworkers (87) studied 10 subjects, aged 60 to 75 years, who cycled at 75 watts to exhaustion. Ten minutes after exercising, quadriceps twitch force, achieved by stimulating the femoral nerve, fell to 64% of baseline. Diaphragmatic twitch pressure, achieved by stimulating the phrenic nerves, did not change. The authors conclude that exercise to exhaustion causes fatigue of the quadriceps, but not of the diaphragm, in healthy elderly subjects. Diagnostic Studies
As a means of monitoring muscle function, Harris and coworkers (88) measured twitch tension generated by the adductor pollicis in response to magnetic stimulation of the ulnar nerve. Twitch tensions were lower in 12 critically ill patients (4.2 N) than in 6 patients undergoing minor surgery (5.8 N), 20 young healthy subjects (6.9 N), and 12 elderly healthy subjects (7.1 N). Close agreement was found between twitch tensions generated with magnetic and electrical stimulators (6.3 and 6.9 N). The authors conclude that muscle strength can be assessed
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by measuring twitch tension generated by the adductor pollicis in response to stimulation of the ulnar nerve. Stefanutti and coworkers (89) evaluated the usefulness of the nasal pressure during a sniff as a measure of inspiratory muscle strength. Of 126 patients, 10 could not perform a maximum inspiratory pressure maneuver but they could sniff. In 92 patients with neuromuscular disorders, measurements of inspiratory muscle strength with the sniff and conventional technique showed good agreement (54 and 52% predicted). In 24 patients with skeletal disorders, values were higher with the sniff than with the conventional technique (70 and 61% of predicted). The authors conclude that measuring the nasal pressure during a sniff can assess inspiratory muscle strength. The increase in transdiaphragmatic pressure achieved by transcutaneous stimulation of phrenic nerves has the advantage of being independent of a patient’s volition. In 25 newborn infants, Rafferty and coworkers (90) compared two means of delivering a magnetic stimulus to the phrenic nerves. Stimulation of the phrenic nerve roots with a probe placed over the cervical spine produced a transdiaphragmatic pressure of 2.5 cm H2O. With probes over the anterolateral portion of the neck, stimulation produced a transdiaphragmatic pressure of 4.5 cm H2O. The authors conclude that stimulation of the phrenic nerves with anterolateral magnetic stimulation may provide a useful method of assessing diaphragmatic function in newborn infants. Respiratory Muscle Involvement in Clinical Disorders
Patients with Duchenne muscular dystrophy inevitably develop hypoventilation during sleep, but it is difficult to know when to order a polysomnogram. In 19 patients, Hukins and Hillman (91) assessed the ability of daytime pulmonary function to predict nighttime desaturation. An FEV1 of less than 40% had a sensitivity of 91% and a specificity of 50%; equivalent values for PCO2 of 45 mm Hg were 91 and 75%, and for a base excess exceeding 4 mmol per liter 55 and 44%. Noninvasive ventilation over one year achieved a 5-torr fall in daytime PCO2 despite a 200-ml decrease in FEV1. The authors conclude that polysomnography should be performed in patients with Duchenne muscular dystrophy when PCO2 rises above 45 mm Hg, especially when base excess exceeds 4 mmol per liter, and the lower daytime PCO2 with nighttime ventilation suggests that sleep hypoventilation contributes to the development of respiratory failure. Transection of the cervical cord causes paralysis of the abdominal muscles. By transcutaneously stimulating the thoracic nerve roots at T10, Estenne and coworkers (92) investigated the residual capability of the abdominal muscles of eight patients with C5–C7 quadriplegia to generate pressure. With maximal stimulation, gastric pressure increased to 30 cm H2O (39% of the value in healthy subjects). On ultrasonography, the abdominal muscles of patients were 32% thinner than in healthy subjects, and the width correlated with gastric pressure. During forced expiration, stimulation of the abdominal muscles increased esophageal pressure and all but two patients developed an increase in expiratory flow. The authors conclude that quadriplegic patients have atrophic abdominal muscles, and that the increase in intrathoracic pressure with external stimulation should be sufficient to clear airway secretions. To investigate the consequences of abdominal muscle paralysis, Gorini and coworkers (93) studied seven patients with paraplegia secondary to complete transection at T6–T7. When inhaling CO2, patients increased minute ventilation to the same level as healthy control subjects but their breathing was rapid and shallow. Hypercapnia caused control subjects to lower
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transpulmonary pressure and abdominal volume at end expiration (without changing ribcage volume), indicating recruitment of the abdominal muscles. In the patients, hypercapnia produced a lesser fall in transpulmonary pressure at end expiration and ribcage volume decreased, indicating recruitment of the ribcage expiratory muscles. The authors conclude that the respiratory controllers in patients with abdominal muscle paralysis alter output to maintain constant minute ventilation. To determine the role of pain in causing respiratory muscle dysfunction after upper abdominal surgery, Vassilakopoulos and coworkers (94) randomized 50 patients to analgesia (pethedine) or placebo. Inspiratory muscle strength, assessed as mouth pressure during a sniff, fell to 42 cm H2O after surgery (a fall of 40%). With analgesia, pressure was 56 cm H2O. Maximal expiratory pressure moved in the same direction, but was not significant. The authors conclude that pain contributes to the inspiratory muscle weakness that follows upper abdominal surgery.
PULMONARY FUNCTION TESTING Equipment and Techniques
The performance of spirometers and peak expiratory flow meters is tested with pump systems, but the input signal and output profile can differ with certain flow profiles. Miller and coworkers (95) developed a mathematical model of wave action within a pump and compared the recorded flow profiles with both the input profiles and the outputs predicted by the model. With a pneumotachograph on its own, recorded flow for seven flow profiles was 2.4% higher than the input flow of the pump. With a 32-cm upstream extension tube in place, recorded flow was 6.6% higher than the pump’s input flow. With a mini-Wright meter, flow was 6.1% below input flow. The authors conclude that outflow from pump systems can differ from the input waveform depending on the operating configurations. Dubois (96) recalls the development of the body plethymograph for measuring airway resistance. Hyatt (97) recalls the development of the flow–volume loop. Forster (98) recalls the development of the technique for measuring diffusing capacity. Stead (99) recalls the early use of esophageal pressure measurements for studying lung elasticity. Quality Control
Because an FVC maneuver takes as long as 20 seconds and is physically demanding, the forced expired volume in 6 seconds (FEV6) has been proposed as a surrogate. In 337 patients with spirometric tests meeting ATS criteria, Swanney and coworkers (100) assessed the agreement between the two measures. With FEV1/FVC as a gold standard for airway obstruction, FEV1/FEV6 had a sensitivity of 95% and a specificity of 97%. Reproducibility of FEV6 was superior to that of FVC. The authors conclude that FEV6 is a reliable alternative to FVC for measuring airway obstruction. As part of a study of asthma and COPD in subjects older than 65 years, Bellia and coworkers (101) assessed the quality control of spirometry performed according to ATS guidelines. At least three acceptable spirometry curves were obtained in 508 of 607 patients with a history of asthma or COPD, and in 747 of 912 subjects without such a history. Average reproducibility for FEV1 was about 60 ml for both groups. The proportion of reproducible tests ranged between 96% for FEV1 in the control subjects to 88% for forced vital capacity in the patients. Factors predicting a decreased rate of acceptability in-
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cluded cognitive impairment, limited education, and impaired performance on a 6-minute walk test. Factors predicting poor reproducibility included male gender and age. The authors conclude that a quality control program can achieve highly reproducible spirometry in elderly subjects. Normative Values
Natural cubic splines can be used to develop normative data on lung function. In 1,039 normal subjects, Pistelli and coworkers (102) used this approach to derive reference values for slow vital capacity and flow–volume curve indices. Body mass index, height, and age were important predictors of lung function. Unlike conventional reference equations, natural cubic splines provided smooth equation curves over the entire age span, with no jumps or angled points. The authors conclude that natural cubic splines provide smooth continuous predictions of lung function that are linear in the extreme age intervals. To determine the influence of ethnic background on pulmonary function, Korotzer and coworkers (103) studied healthy nonsmokers living in the United States and aged 22 to 33 years. The 80 subjects were stratified according to sex, and European and Asian descent. Values for FEV1, forced vital capacity, and alveolar volume were lower in those of Asian descent, whereas diffusing capacity did not differ. Differences could not be attributed to length of residence in the United States, activity, or anthropometric measurements, indicating that they represent a true physiologic difference. The authors conclude that ethnic origin should be taken into account when interpreting pulmonary function tests in individuals of Asian descent. Epidemiology Studies
In epidemiological studies of asthma in different countries, cross-cultural differences in subjective recognition and reporting of symptoms pose a challenge. Sunyer and coworkers (104) studied 16,635 subjects from 15 countries in the European Community Respiratory Health Study. Subjects answered a questionnaire, and underwent allergy tests and methacholine provocation. Exploratory factor analysis identified how symptoms were grouped, using data from the UK. Later, confirmatory factor analysis of the prespecified structure for the UK was assessed for each country, increasing at each step the number of parameters forced to be equal to the UK and assessing the goodness of fit. When the load of each symptom in the corresponding factor was prespecified, all countries except Spain showed an adequate fit. The authors conclude that the questionnaire translated into several languages shows high internal consistency, suggesting that international comparisons are not affected by cross-cultural variations in the reporting of symptoms. The change in FEV1 over time is widely used in outcomes research. Compared with the “true” slope of FEV1 over time in an infinite population, the measured slope of FEV1 includes biological variation and measurement errors, which can be minimized by increasing the number of subjects, the frequency of measurements, and years of follow-up. From a longitudinal survey, Wang and coworkers (105) calculated intra- and intersubject variability under different conditions and developed a formula for estimating the maximum error in the measurements. Presented tables provide data on the magnitude of differences in the slope of FEV1 that can be reliably detected between groups, the number of subjects needed to detect an anticipated difference, and other variables. The authors conclude that the presented tables provide guidance to investigators doing longitudinal studies involving spirometry.
Predicting Postoperative Complications
Because a decrease in the pulmonary capillary bed available for gas exchange may predispose to complications after surgery, Wang and coworkers (106) measured diffusing capacity at rest and during exercise in 57 patients undergoing resection for lung cancer. Patients developing complications had a lower diffusing capacity at rest, a smaller increase in diffusing capacity during steady-state exercise at 70% of maximum workload, and a lower maximal oxygen consumption than did patients without complications. The best predictor of complications was the failure of diffusing capacity while exercising to increase by more than 10% of resting value: sensitivity, 78%; specificity, 100%. The authors conclude that measuring diffusing capacity during exercise is useful in predicting complications in patients undergoing resection surgery for lung cancer. In Heart Failure
Because patients with chronic left ventricular failure commonly develop orthopnea, Yap and coworkers (107) measured respiratory mechanics in the sitting and supine posture in 10 patients shortly after they recovered from acute ventricular failure. While seated, the patients had smaller lung volumes, a normal FEV1/FVC ratio (81%), and slightly increased respiratory resistance (3.4 versus 2.6 cm H2O per liter per second in control subjects). After being supine for five minutes, the patients developed a 76% increase in specific resistance (versus 17% in the control subjects), despite developing smaller falls in lung volume. The muscarinic antagonist, ipratropium, had minimal effect on the change in resistance. The authors conclude that patients with chronic left ventricular failure develop a large increase in airflow resistance when supine, which is not explained by a decrease in lung volume and is not caused by vagally induced bronchoconstriction. Closing Volume and Gas Exchange
To determine whether closing volume influences the postural change in oxygenation in patients with unilateral lung disease, Choe and coworkers (108) measured the alveolar-to-arterial PO2 gradient in 44 patients in the supine and right and left lateral decubitus positions. With the good lung in the dependent position, 59% of the patients developed an increase in PO2; the opposite occurred in the remaining patients. In 16 patients, the difference in PO2 between having the good or bad lung dependent was related to the difference in fractional ventilation of the normal lung between the supine and dependent positions (r 0.64), and the latter was also related to closing volume (r 0.60). The authors conclude that closing volume influences the change in oxygenation with lateral dependency in patients with unilateral lung disease. Lung Sounds
To determine whether aging alters lung sounds, Gross and coworkers (109) recorded sounds from four locations on the posterior thorax in 162 subjects. The recordings were analyzed by fast Fourier transformation and power at midfrequency bands (300 to 600 Hz) and low-frequency bands (60 to 330 Hz) was measured. The ratio of relative power in the mid- and low-frequency bands differed between men and women, but not between smokers and nonsmokers. A slight increase in relative power in the midfrequency band was seen with age.
NITRIC OXIDE Of the three isoforms of nitric oxide synthase (NOS-1 or neuronal; NOS-2 or inducible; and NOS-3 or endothelial), it is not
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known which is responsible for baseline levels of exhaled nitric oxide. Steudel and coworkers (110) studied mice with a congenital absence of each isoform. Compared with the gaseous production of exhaled nitric oxide in wild-type mice, NOS-1-deficient mice exhaled 64% more, NOS-2-deficient mice exhaled 9% less, and NOS-3-deficient mice exhaled more than twice the amount. Inhibition of nitric oxide synthase with L-NAME decreased exhaled production rate of nitric oxide in wild-type and NOS-3-deficient mice, but not in NOS-2-deficient mice. Administration of L-arginine increased exhaled nitric oxide production rate in all animals, except in NOS-2deficient mice. The authors conclude that NOS-2-deficient mice, that is, mice whose genotype does not include the NOS2 gene, lacked substrate- and inhibitor-regulated changes of nitric oxide exhalation, indicating that NOS-2 is important for baseline levels of exhaled nitric oxide. To determine the relationship between PO2 and nitric oxide function, Tsuchiya and coworkers (111) did three sets of experiments. The effect of nitric oxide in causing in vitro relaxation of aortic specimens was decreased by 68% when PO2 was 480 versus 28 mm Hg. In 23 nonsmokers, exhaled nitric oxide was reciprocally correlated with the alveolar-to-arterial PO2 gradient (r 0.53). In 21 nonsmokers, inhalation of pure oxygen during mechanical ventilation produced a decrease in exhaled nitric oxide and an increase in the alveolarto-arterial PO2 gradient. The authors conclude that a positive relationship exists between exhaled nitric oxide and the efficiency of arterial oxygenation. In 75 patients with cystic fibrosis, Grasemann and coworkers (112) examined the relationship between exhaled nitric oxide and the size of an AAT repeat polymorphism in intron 20 of the nitric oxide synthase 1 gene. Patients with a high number of AAT repeats (both alleles having at least 12 repeats) at this locus had higher concentrations of exhaled nitric oxide than patients with a low number of repeats (at least one allele having less than 12 repeats): 4.0 and 6.4 ppb. The airways of patients with a high number of AAT repeats were more commonly colonized with Pseudomonas aeruginosa. The authors conclude that the gene for nitric oxide synthase 1 is not only associated with variability in the level of exhaled nitric oxide in patients with cystic fibrosis but also with P. aeruginosa colonization of the airways. In a study of 40 lung transplant recipients, Gabbay and coworkers (113) asked, “In patients with bronchiolitis obliterans, does an increase in exhaled nitric oxide reflect airway inflammation?” Exhaled nitric oxide was elevated in eight patients with bronchiolitis obliterans syndrome (20 ppb) and in six patients with airway infection (24.7 ppb), but was normal in six patients with acute rejection (13.4 ppb) and in 20 recipients of a lung transplant who were stable (12.5 ppb). Inducible nitric oxide synthase was expressed in the bronchial epithelium of patients with bronchiolitis obliterans and bacterial infection, and it was correlated with exhaled nitric oxide (r2 0.79). Expression of constitutive nitric oxide synthase was decreased in patients with bronchiolitis obliterans syndrome, but not in the other groups. The authors conclude that exhaled nitric oxide arises primarily from inducible nitric oxide synthase in the epithelium, and, because the level reflects the degree of airway inflammation, serial measurements might identify bronchiolitis obliterans while it is still at a reversible stage.
BRONCHOSCOPY To assess the extent to which patients undergoing fiberoptic bronchoscopy experience pain and to identify factors influencing pain, Lechtzin and coworkers (114) prospectively studied
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481 patients. Pain control was rated excellent in 36% of patients, and fair or poor in 10%. Factors in patients associated with excellent pain control included excellent health (odds ratio [OR] 6.3), more education (OR 1.7), and absence of asthma (OR 2.9). Factors in the delivery of care associated with excellent pain control included not being bothered by inserting the scope (OR 3.7), no memory of the procedure (OR 2.3), and better information about the procedure (OR 1.6). The authors conclude that physicians can decrease pain during bronchoscopy by providing better information to patients about the procedure, achieving better amnesia, and avoiding pain on inserting the bronchoscope. During uncomplicated bronchoscopy, PO2 usually falls by 10–20 mm Hg. To determine whether CPAP would prevent hypoxemia during fiberoptic bronchoscopy, Maitre and coworkers (115) did a randomized double-blind trial of CPAP versus supplemental oxygen alone in 36 hypoxemic patients (PO2/FIO2 ratio less than 300 mm Hg). The lowest oxygen saturation during bronchoscopy was 89% in the oxygen group and 94% in the CPAP group. By 15 minutes after the procedure, PO2 increased by 11% in the CPAP group and fell by 15% in the oxygen group. The authors conclude that use of CPAP minimizes worsening hypoxemia in hypoxemic patients undergoing bronchoscopy and prevents subsequent respiratory failure. To assess the effects of preoperative radiotherapy and 5-fluorouracil on bronchoscopic and lung function in patients with proximal esophageal cancer, Riedel and coworkers (116) prospectively studied 77 consecutive patients. Of 13 patients with apparent tumor invasion of the airways, histological proof was obtained in only 1. Bronchoscopy was falsely negative in six patients with airway invasion at surgery. Radiotherapy and 5-fluorouracil did not alter pulmonary function, but it produced microscopic inflammatory changes on bronchoscopic specimens. The authors conclude that bronchoscopy was falsely negative in 9% of patients with proximal esophageal cancer. Because little information exists concerning airway complications following lung transplantation in children, Kaditis and coworkers (117) reviewed their experience in 53 patients (mean age, 14 years). Major anastomotic airway complications requiring intervention occurred in 4% of heart–lung transplants and 25% of the lung transplant patients. Granulation tissue occluding the airway occurred in four patients; it was treated with forceps resection, laser ablation, or balloon dilatation. Fibrotic strictures occurred in three patients, and were treated with silicone stents, laser ablation, or balloon dilatation. Bronchomalacia or diffuse stricture below the anastomosis occurred in two patients, and required a metal stent. The authors conclude that major anastomotic airway complications are more common in pediatric lung transplant patients than in adults. Harrow and coworkers (118) prospectively assessed the value of transbronchial needle aspiration for staging bronchogenic carcinoma. Positive aspirates were found in 62% of 81 patients with small cell carcinoma and in 48% of patients with non-small cell carcinoma. Of the 360 patients, transbronchial needle aspiration precluded thoracic surgery in 29% of patients, and it was the sole source of diagnosis in 18% of cases. Positive results were more likely with histologic than with cytologic aspirates (57 and 41%), and with tumors on the right side. The authors conclude that transbronchial needle aspiration is likely to provide positive results when nodes are large and on the right side, when a histology needle is used, and in patients with small cell carcinoma. References 1. Gottlieb DJ, Yao Q, Redline S, Ali T, Mahowald MW. Does snoring
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predict sleepiness independently of apnea and hypopnea frequency? Am J Respir Crit Care Med 2000;162:1512–1517. O’Connor C, Thornley KS, Hanly PJ. Gender differences in the polysomnographic features of obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:1465–1472. Findley L, Smith C, Hooper J, Dineen M, Suratt PM. Treatment with nasal CPAP decreases automobile accidents in patients with sleep apnea. Am J Respir Crit Care Med 2000;161:857–859. Masa JF, Rubio M, Findley LJ. Habitually sleepy drivers have a high frequency of automobile crashes associated with respiratory disorders during sleep. Am J Respir Crit Care Med 2000;162:1407–1412. Schellenberg JB, Maislin G, Schwab RJ. Physical findings and the risk for obstructive sleep apnea. The importance of oropharyngeal structures. Am J Respir Crit Care Med 2000;162:740–748. Parra O, Arboix A, Bechich S, Garcia-Eroles L, Montserrat JM, Lopez JA, Ballester E, Guerra JM, Sopena JJ. Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit Care Med 2000;161:375–380. Edwards N, Blyton DM, Kirjavainen T, Kesby GJ, Sullivan CE. Nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in preeclampsia. Am J Respir Crit Care Med 2000;162:252–257. Morrell MJ, Finn L, Kim H, Peppard PE, Badr MS, Young T. Sleep fragmentation, awake blood pressure, and sleep-disordered breathing in a population-based study. Am J Respir Crit Care Med 2000; 162:2091–2096. Peker Y, Hedner J, Kraiczi H, Loth S. Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med 2000;162:81–86. Wessendorf TE, Thilmann AF, Wang YM, Schreiber A, Konietzko N, Teschler H. Fibrinogen levels and obstructive sleep apnea in ischemic stroke. Am J Respir Crit Care Med 2000;162:2039–2042. Shamsuzzaman AS, Somers VK. Fibrinogen, stroke, and obstructive sleep apnea: an evolving paradigm of cardiovascular risk. Am J Respir Crit Care Med 2000;162:2018–2020. Grote L, Kraiczi H, Hedner J. Reduced - and 2-adrenergic vascular response in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2000;162:1480–1487. Kraiczi H, Hedner J, Peker Y, Grote L. Comparison of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan for antihypertensive treatment in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:1423–1428. Samet JM, Javier NF, Punjabi NM. Sleep-disordered breathing and hypertension: more research is still needed. Am J Respir Crit Care Med 2000;161:1409–1411. Duchna HW, Guilleminault C, Stoohs RA, Faul JL, Moreno H, Hoffman BB, Blaschke TF. Vascular reactivity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2000;161:187–191. Carley DW, Berecek K, Videnovic A, Radulovacki M. Sleep-disordered respiration in phenotypically normotensive, genetically hypertensive rats. Am J Respir Crit Care Med 2000;162:1474–1479. Trinder J, Merson R, Rosenberg JI, Fitzgerald F, Kleiman J, Douglas BT. Pathophysiological interactions of ventilation, arousals, and blood pressure oscillations during Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med 2000;162:808–813. Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W, Grimminger F. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000;162:566–570. Ip MS, Lam B, Chan LY, Zheng L, Tsang KW, Fung PC, Lam WK. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000;162:2166–2171. Sforza E, Bacon W, Weiss T, Thibault A, Petiau C, Krieger J. Upper airway collapsibility and cephalometric variables in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:347–352. King ED, O’Donnell CP, Smith PL, Schwartz AR. A model of obstructive sleep apnea in normal humans. Role of the upper airway. Am J Respir Crit Care Med 2000;161:1979–1984. Malhotra A, Fogel RB, Edwards JK, Shea SA, White DP. Local mechanisms drive genioglossus activation in obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:1746–1749. Malhotra A, Pillar G, Fogel RB, Beauregard J, Edwards JK, Slamowitz DI, Shea SA, White DP. Genioglossal but not palatal muscle activity relates closely to pharyngeal pressure. Am J Respir Crit Care Med 2000;162:1058–1062.
1373 24. Pillar G, Malhotra A, Fogel R, Beauregard J, Schnall R, White DP. Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender. Am J Respir Crit Care Med 2000; 162:1627–1632. 25. O’Donnell CP, Schwartz AR, Smith PL. Upper airway collapsibility: the importance of gender and adiposity. Am J Respir Crit Care Med 2000;162:1606–1607. 26. Shea SA, Akahoshi T, Edwards JK, White DP. Influence of chemoreceptor stimuli on genioglossal response to negative pressure in humans. Am J Respir Crit Care Med 2000;162:559–565. 27. Series F, Straus C, Demoule A, Attali V, Arnulf I, Derenne JP, Similowski T. Assessment of upper airway dynamics in awake patients with sleep apnea using phrenic nerve stimulation. Am J Respir Crit Care Med 2000;162:795–800. 28. Solin P, Roebuck T, Johns DP, Walters EH, Naughton MT. Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure. Am J Respir Crit Care Med 2000; 162:2194–2200. 29. Spengler CM, Shea SA. Sleep deprivation per se does not decrease the hypercapnic ventilatory response in humans. Am J Respir Crit Care Med 2000;161:1124–1128. 30. Ayas NT, Brown R, Shea SA. Hypercapnia can induce arousal from sleep in the absence of altered respiratory mechanoreception. Am J Respir Crit Care Med 2000;162:1004–1008. 31. Spengler CM, Shea SA. Endogenous circadian rhythm of pulmonary function in healthy humans. Am J Respir Crit Care Med 2000;162: 1038–1046. 32. Rees K, Kingshott RN, Wraith PK, Douglas NJ. Frequency and significance of increased upper airway resistance during sleep. Am J Respir Crit Care Med 2000;162:1210–1214. 33. Black JE, Guilleminault C, Colrain IM, Carrillo O. Upper airway resistance syndrome. Central electroencephalographic power and changes in breathing effort. Am J Respir Crit Care Med 2000;162:406–411. 34. Guilleminault C, Chowdhuri S. Upper airway resistance syndrome is a distinct syndrome. Am J Respir Crit Care Med 2000;161:1412–1413. 35. Douglas NJ. Upper airway resistance syndrome is not a distinct syndrome. Am J Respir Crit Care Med 2000;161:1413–1416. 36. Guilleminault C, Chowdhuri S. Rebuttal. Am J Respir Crit Care Med 2000;161:1415. 37. Douglas NJ. Rebuttal. Am J Respir Crit Care Med 2000;161:1415–1416. 38. Arnulf I, Similowski T, Salachas F, Garma L, Mehiri S, Attali V, BehinBellhesen V, Meininger V, Derenne JP. Sleep disorders and diaphragmatic function in patients with amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2000;161:849–856. 39. Goh DY, Galster P, Marcus CL. Sleep architecture and respiratory disturbances in children with obstructive sleep apnea. Am J Respir Crit Care Med 2000;162:682–686. 40. Berger PJ, Skuza EM, Brodecky V, Cranage SM, Adamson TM, Wilkinson MH. Unusual respiratory response to oxygen in an infant with repetitive cyanotic episodes. Am J Respir Crit Care Med 2000; 161:2107–2111. 41. Redline S, Kapur VK, Sanders MH, Quan SF, Gottlieb DJ, Rapoport DM, Bonekat WH, Smith PL, Kiley JP, Iber C. Effects of varying approaches for identifying respiratory disturbances on sleep apnea assessment. Am J Respir Crit Care Med 2000;161:369–374. 42. Zerah-Lancner F, Lofaso F, d’Ortho MP, Delclaux C, Goldenberg F, Coste A, Housset B, Harf A. Predictive value of pulmonary function parameters for sleep apnea syndrome. Am J Respir Crit Care Med 2000;162:2208–2212. 43. Portier F, Portmann A, Czernichow P, Vascaut L, Devin E, Benhamou D, Cuvelier A, Muir JF. Evaluation of home versus laboratory polysomnography in the diagnosis of sleep apnea syndrome. Am J Respir Crit Care Med 2000;162:814–818. 44. Weese-Mayer DE, Corwin MJ, Peucker MR, Di Fiore JM, Hufford DR, Tinsley LR, Neuman MR, Martin RJ, Brooks LJ, Davidson Ward SL, Lister G, Willinger M. Comparison of apnea identified by respiratory inductance plethysmography with that detected by endtidal CO2 or thermistor. The CHIME Study Group. Am J Respir Crit Care Med 2000;162:471–480. 45. Argod J, Pepin JL, Smith RP, Levy P. Comparison of esophageal pressure with pulse transit time as a measure of respiratory effort for scoring obstructive nonapneic respiratory events. Am J Respir Crit Care Med 2000;162:87–93. 46. Chervin RD, Aldrich MS. Sleep onset REM periods during multiple sleep latency tests in patients evaluated for sleep apnea. Am J Respir Crit Care Med 2000;161:426–431. 47. Kingshott RN, Vennelle M, Hoy CJ, Engleman HM, Deary IJ, Douglas
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NJ. Predictors of improvements in daytime function outcomes with CPAP therapy. Am J Respir Crit Care Med 2000;161:866–871. Series F. Accuracy of an unattended home CPAP titration in the treatment of obstructive sleep apnea. Am J Respir Crit Care Med 2000; 162:94–97. Mehta S, Liu PP, Fitzgerald FS, Allidina YK, Douglas BT. Effects of continuous positive airway pressure on cardiac volumes in patients with ischemic and dilated cardiomyopathy. Am J Respir Crit Care Med 2000;161:128–134. Schneider H, O’Hearn DJ, Leblanc K, Smith PL, O’Donnell CP, Eisele DW, Peter JH, Schwartz AR. High-flow transtracheal insufflation treats obstructive sleep apnea. A pilot study. Am J Respir Crit Care Med 2000;161:1869–1876. Davies RJ, Stradling JR. The efficacy of nasal continuous positive airway pressure in the treatment of obstructive sleep apnea syndrome is proven. Am J Respir Crit Care Med 2000;161:1775–1776. Wright J, Sheldon T. The efficacy of nasal continuous positive airway pressure in the treatment of obstructive sleep apnea syndrome is not proven. Am J Respir Crit Care Med 2000;161:1776–1778. Davies RJ, Stradling JR. Rebuttal. Am J Respir Crit Care Med 2000;161:1778. Wright J, Sheldon T. Rebuttal. Am J Respir Crit Care Med 2000;161: 1778. Sunderram J, Parisi RA, Strobel RJ. Serotonergic stimulation of the genioglossus and the response to nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000;162:925–929. Henke KG, Frantz DE, Kuna ST. An oral elastic mandibular advancement device for obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:420–425. Bloch KE, Iseli A, Zhang JN, Xie X, Kaplan V, Stoeckli PW, Russi EW. A randomized, controlled crossover trial of two oral appliances for sleep apnea treatment. Am J Respir Crit Care Med 2000;162: 246–251. Bettega G, Pepin JL, Veale D, Deschaux C, Raphael B, Levy P. Obstructive sleep apnea syndrome. Fifty-one consecutive patients treated by maxillofacial surgery. Am J Respir Crit Care Med 2000; 162:641–649. Czapla MA, Gozal D, Alea OA, Beckerman RC, Zadina JE. Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine. Am J Respir Crit Care Med 2000;162: 994–999. Lee SD, Nakano H, Gosselin LE, Krasney JA, Schlenker EH, Farkas GA. Endogenous opioids modulate ventilation and peak oxygen consumption in obese Zucker rats. Am J Respir Crit Care Med 2000; 162:1009–1015. Ohtake PJ, Simakajornboon N, Fehniger MD, Xue YD, Gozal D. N-Methyl-D-aspartate receptor expression in the nucleus tractus solitarii and maturation of hypoxic ventilatory response in the rat. Am J Respir Crit Care Med 2000;162:1140–1147. Bouferrache B, Filtchev S, Leke A, Marbaix-Li Q, Freville M, Gaultier C. The hyperoxic test in infants reinvestigated. Am J Respir Crit Care Med 2000;161:160–165. Jubran A, Tobin MJ. Effect of isocapnic hypoxia on variational activity of breathing. Am J Respir Crit Care Med 2000;162:1202–1209. Kijima M, Isono S, Nishino T. Modulation of swallowing reflex by lung volume changes. Am J Respir Crit Care Med 2000;162:1855–1858. Gozal D, Simakajornboon N. Passive motion of the extremities modifies alveolar ventilation during sleep in patients with congenital central hypoventilation syndrome. Am J Respir Crit Care Med 2000;162: 1747–1751. Manning HL, Leiter JC. Respiratory control and respiratory sensation in a patient with a ganglioglioma within the dorsocaudal brain stem. Am J Respir Crit Care Med 2000;161:2100–2106. Robinson TD, Freiberg DB, Regnis JA, Young IH. The role of hypoventilation and ventilation–perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1524–1529. Moy ML, Woodrow WJ, Sparrow D, Israel E, Schwartzstein RM. Quality of dyspnea in bronchoconstriction differs from external resistive loads. Am J Respir Crit Care Med 2000;162:451–455. Lansing RW, Im BS, Thwing JI, Legedza AT, Banzett RB. The perception of respiratory work and effort can be independent of the perception of air hunger. Am J Respir Crit Care Med 2000;162:1690–1696. Killian KJ, Watson R, Otis J, St Amand TA, O’Byrne PM. Symptom perception during acute bronchoconstriction. Am J Respir Crit Care Med 2000;162:490–496. Lavietes MH, Sanchez CW, Tiersky LA, Cherniack NS, Natelson BH.
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Psychological profile and ventilatory response to inspiratory resistive loading. Am J Respir Crit Care Med 2000;161:737–744. Nishino T, Ide T, Sudo T, Sato J. Inhaled furosemide greatly alleviates the sensation of experimentally induced dyspnea. Am J Respir Crit Care Med 2000;161:1963–1967. Leduc D, Brunko E, De Troyer A. Response of the canine inspiratory intercostal muscles to chest wall vibration. Am J Respir Crit Care Med 2000;161:510–516. Ho CY, Gu Q, Hong JL, Lee LY. Prostaglandin E2 enhances chemical and mechanical sensitivities of pulmonary C fibers in the rat. Am J Respir Crit Care Med 2000;162:528–533. Davenport PW, Cruz M, Stecenko AA, Kifle Y. Respiratory-related evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med 2000;161:1830–1835. Banzett RB, Dempsey JA, O’Donnell DE, Wamboldt MZ. Symptom perception and respiratory sensation in asthma. Am J Respir Crit Care Med 2000;162:1178–1182. Campbell EJM. A being breathing thoughtful breaths. Am J Respir Crit Care Med 2000;162:2027–2028. Attal P, Lambert F, Marchand-Adam S, Bobin S, Pourny JC, Chemla D, Lecarpentier Y, Coirault C. Severe mechanical dysfunction in pharyngeal muscle from adult mdx mice. Am J Respir Crit Care Med 2000;162:278–281. Gea J, Hamid Q, Czaika G, Zhu E, Mohan-Ram V, Goldspink G, Grassino A. Expression of myosin heavy-chain isoforms in the respiratory muscles following inspiratory resistive breathing. Am J Respir Crit Care Med 2000;161:1274–1278. Stofan DA, Callahan LA, Di Marco AF, Nethery DE, Supinski GS. Modulation of release of reactive oxygen species by the contracting diaphragm. Am J Respir Crit Care Med 2000;161:891–898. Reid WD, Belcastro AN. Time course of diaphragm injury and calpain activity during resistive loading. Am J Respir Crit Care Med 2000; 162:1801–1806. Fujimura N, Sumita S, Narimatsu E, Nakayama Y, Shitinohe Y, Namiki A. Effects of isoproterenol on diaphragmatic contractility in septic peritonitis. Am J Respir Crit Care Med 2000;161:440–446. Fujimura N, Sumita S, Aimono M, Masuda Y, Shichinohe Y, Narimatsu E, Namiki A. Effect of free radical scavengers on diaphragmatic contractility in septic peritonitis. Am J Respir Crit Care Med 2000;162:2159–2165. Al Bilbeisi F, McCool FD. Diaphragm recruitment during nonrespiratory activities. Am J Respir Crit Care Med 2000;162:456–459. Mador MJ, Kufel TJ, Pineda LA, Sharma GK. Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:118–123. Mador MJ, Kufel TJ, Pineda L. Quadriceps fatigue after cycle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:447–453. Mador MJ, Kufel TJ, Pineda LA. Quadriceps and diaphragmatic function after exhaustive cycle exercise in the healthy elderly. Am J Respir Crit Care Med 2000;162:1760–1766. Harris ML, Luo YM, Watson AC, Rafferty GF, Polkey MI, Green M, Moxham J. Adductor pollicis twitch tension assessed by magnetic stimulation of the ulnar nerve. Am J Respir Crit Care Med 2000;162: 240–245. Stefanutti D, Benoist MR, Scheinmann P, Chaussain M, Fitting JW. Usefulness of sniff nasal pressure in patients with neuromuscular or skeletal disorders. Am J Respir Crit Care Med 2000;162:1507–1511. Rafferty GF, Greenough A, Dimitriou G, Kavadia V, Laubscher B, Polkey MI, Harris ML, Moxham J. Assessment of neonatal diaphragm function using magnetic stimulation of the phrenic nerves. Am J Respir Crit Care Med 2000;162:2337–2340. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000; 161:166–170. Estenne M, Pinet C, De Troyer A. Abdominal muscle strength in patients with tetraplegia. Am J Respir Crit Care Med 2000;161:707–712. Gorini M, Corrado A, Aito S, Ginanni R, Villella G, Lucchesi G, De Paola E. Ventilatory and respiratory muscle responses to hypercapnia in patients with paraplegia. Am J Respir Crit Care Med 2000;162: 203–208. Vassilakopoulos T, Mastora Z, Katsaounou P, Doukas G, Klimopoulos S, Roussos C, Zakynthinos S. Contribution of pain to inspiratory muscle dysfunction after upper abdominal surgery: a randomized controlled trial. Am J Respir Crit Care Med 2000;161:1372–1375. Miller MR, Jones B, Xu Y, Pedersen OF, Quanjer PH. Peak expiratory flow profiles delivered by pump systems. Limitations due to wave action. Am J Respir Crit Care Med 2000;161:1887–1896. Dubois AB. Airway resistance. Am J Respir Crit Care Med 2000;162:345–346.
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Year in Review 97. Hyatt RE. How flow met volume in three-dimensional space. Am J Respir Crit Care Med 2000;161:1779–1780. 98. Forster RE. How science happened to me. Am J Respir Crit Care Med 2000;161:1421–1422. 99. Stead WW. The devil is in the details. Am J Respir Crit Care Med 2000;162:775–776. 100. Swanney MP, Jensen RL, Crichton DA, Beckert LE, Cardno LA, Crapo RO. FEV6 is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction. Am J Respir Crit Care Med 2000;162:917–919. 101. Bellia V, Pistelli R, Catalano F, Antonelli-Incalzi R, Grassi V, Melillo G, Olivieri D, Rengo F. Quality control of spirometry in the elderly. The SA.R.A. Study. Am J Respir Crit Care Med 2000;161:1094–1100. 102. Pistelli F, Bottai M, Viegi G, Di Pede F, Carrozzi L, Baldacci S, Pedreschi M, Giuntini C. Smooth reference equations for slow vital capacity and flow–volume curve indexes. Am J Respir Crit Care Med 2000; 161:899–905. 103. Korotzer B, Ong S, Hansen JE. Ethnic differences in pulmonary function in healthy nonsmoking Asian-Americans and European-Americans. Am J Respir Crit Care Med 2000;161:1101–1108. 104. Sunyer J, Basagana X, Burney P, Anto JM. International assessment of the internal consistency of respiratory symptoms. European Community Respiratory Health Study (ECRHS). Am J Respir Crit Care Med 2000;162:930–935. 105. Wang ML, Gunel E, Petsonk EL. Design strategies for longitudinal spirometry studies: study duration and measurement frequency. Am J Respir Crit Care Med 2000;162:2134–2138. 106. Wang JS, Abboud RT, Evans KG, Finley RJ, Graham BL. Role of CO diffusing capacity during exercise in the preoperative evaluation for lung resection. Am J Respir Crit Care Med 2000;162:1435–1444. 107. Yap JC, Moore DM, Cleland JG, Pride NB. Effect of supine posture on respiratory mechanics in chronic left ventricular failure. Am J Respir Crit Care Med 2000;162:1285–1291. 108. Choe KH, Kim YT, Shim TS, Lim CM, Lee SD, Koh Y, Kim WS, Kim DS, Ryu JS, Kim WD. Closing volume influences the postural effect on oxygenation in unilateral lung disease. Am J Respir Crit Care Med 2000;161:1957–1962. 109. Gross V, Dittmar A, Penzel T, Schuttler F, von Wichert P. The rela-
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tionship between normal lung sounds, age, and gender. Am J Respir Crit Care Med 2000;162:905–909. Steudel W, Kirmse M, Weimann J, Ullrich R, Hromi J, Zapol WM. Exhaled nitric oxide production by nitric oxide synthase-deficient mice. Am J Respir Crit Care Med 2000;162:1262–1267. Tsuchiya M, Tokai H, Takehara Y, Haraguchi Y, Asada A, Utsumi K, Inoue M. Interrelation between oxygen tension and nitric oxide in the respiratory system. Am J Respir Crit Care Med 2000;162:1257–1261. Grasemann H, Knauer N, Buscher R, Hubner K, Drazen JM, Ratjen F. Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene. Am J Respir Crit Care Med 2000;162:2172–2176. Gabbay E, Walters EH, Orsida B, Whitford H, Ward C, Kotsimbos TC, Snell GI, Williams TJ. Post-lung transplant bronchiolitis obliterans syndrome (BOS) is characterized by increased exhaled nitric oxide levels and epithelial inducible nitric oxide synthase. Am J Respir Crit Care Med 2000;162:2182–2187. Lechtzin N, Rubin HR, Jenckes M, White P, Zhou LM, Thompson DA, Diette GB. Predictors of pain control in patients undergoing flexible bronchoscopy. Am J Respir Crit Care Med 2000;162:440–445. Maitre B, Jaber S, Maggiore SM, Bergot E, Richard JC, Bakthiari H, Housset B, Boussignac G, Brochard L. Continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic patients. A randomized double-blind study using a new device. Am J Respir Crit Care Med 2000;162:1063–1067. Riedel M, Stein HJ, Mounyam L, Zimmermann F, Fink U, Siewert JR. Influence of simultaneous neoadjuvant radiotherapy and chemotherapy on bronchoscopic findings and lung function in patients with locally advanced proximal esophageal cancer. Am J Respir Crit Care Med 2000;162:1741–1746. Kaditis AG, Gondor M, Nixon PA, Webber S, Keenan RJ, Kaye R, Kurland G. Airway complications following pediatric lung and heart–lung transplantation. Am J Respir Crit Care Med 2000;162: 301–309. Harrow EM, Abi-Saleh W, Blum J, Harkin T, Gasparini S, AddrizzoHarris DJ, Arroliga AC, Wight G, Mehta AC. The utility of transbronchial needle aspiration in the staging of bronchogenic carcinoma. Am J Respir Crit Care Med 2000;161:601–607.
