© 2007 American Thoracic Society doi: 10.1164/rccm.200701-043UP
Update in Sleep and Control of Ventilation 2006Departments of 1 Medicine and 2 Physiology, and 3 Centre for Sleep Medicine and Circadian Biology at the University of Toronto, Toronto, Canada; 4 Sleep Research Laboratory of the Toronto Rehabilitation Institute, Toronto, Canada; and 5 Department of Medicine, Toronto General Hospital of the University Health Network, Toronto, Canada Correspondence and requests for reprints should be addressed to Richard L. Horner, Ph.D., Room 6368, Medical Sciences Building, 1 Kings College Circle, Toronto, ON, M5S 1A8 Canada. E-mail: richard.horner{at}utoronto.ca UPPER AIRWAY MOTOR CONTROL Although the upper airway of children with obstructive sleep apnea (OSA) is more collapsible than in control subjects, most children with OSA experience prolonged periods of stable breathing at night. Both anatomic factors and the ability to mount a robust neuromuscular compensatory response to loading are important to the pathogenesis of OSA, with the latter particularly relevant to the ability to restore adequate airflow and sustain stable breathing. Accordingly, Katz and colleagues (1) determined the neuromuscular compensatory pharyngeal dilator muscle responses to airway collapsing pressures by recording genioglossus muscle activity in normal, healthy, sleeping children. The subjects (age range, 9.1–16.4 yr; mean, 11.9 yr; body mass index in the 70th percentile) were placed on +3 cm H2O of continuous positive airway pressure (CPAP), and mask pressure was then varied during sleep to a minimum of –22 cm H2O, with pressures applied for five consecutive breaths and returned to baseline for 30 seconds between interventions. There was wide intersubject variability in the magnitude of the genioglossus muscle responses to airway collapsing pressures in sleep. Importantly, the prominent increases in genioglossus activity in some subjects were associated with increased airflow during loading, increased respiratory rate, and decreased airflow resistance, and in some cases, recovery of normal ventilation without evidence of electrocortical arousal. The authors speculate that this robust pharyngeal dilator muscle response to loading may account for the periods of stable breathing during sleep in some children with OSA, and that the severity of sleep apnea for a given child is influenced by the balance between intrinsic anatomic factors (airway size and stiffness), neuromuscular compensatory responses to loading, and arousal threshold.
The concept of a tonic drive activating respiratory muscles in wakefulness, but not sleep, has been an important and enduring notion in respiratory medicine, not least because it is the root mechanism to understand the effects of sleep on breathing and pathogenesis of sleep-related breathing disorders such as OSA. However, a neurotransmitter substrate that mediates activation of respiratory muscle across sleep–wake states had not been identified. Chan and colleagues (2) determined the role of endogenous
Previous studies modulating pharyngeal muscle activity with pharmacologic approaches have all targeted membrane receptors on pharyngeal motoneurons. Whether modulation of intracellular pathways can increase pharyngeal muscle activity across sleep–wake states, however, had not been investigated but is relevant to pharmacologic treatments of OSA as it may allow for sustained pharyngeal motoneuron activation in sleep despite changes in extracellular neurotransmitters. Using rats instrumented for manipulation of the hypoglossal motor nucleus while recording genioglossus and diaphragm muscle activities, Aoki and coworkers (5) showed that modulation of the cyclic adenosine-3'-5'-monophosphate (cAMP)–protein kinase A pathway at the hypoglossal motor nucleus increased genioglossus muscle activity in wakefulness and non-REM sleep but not in REM sleep. This result emphasizes the consistent finding that REM sleep recruits powerful neural mechanisms that can overcome excitatory motor responses and powerfully suppress genioglossus activity (2). The study also demonstrated a new mechanism in respiratory motor control by which cyclic guanosine-3'-5'-monophosphate (cGMP) at the hypoglossal motor nucleus abolished the normally potent excitatory responses to locally applied serotonin and UPPER AIRWAY ANATOMY Development and validation of techniques to quantitatively image the upper airway are important to investigate the pathophysiology of OSA, and to evaluate potential treatments. Armstrong and colleagues (6) used an endoscopic technique to image upper airway size and shape in real time using optical coherence tomography. The optical probe is placed inside a transparent catheter (3.0 mm outside diameter), which is inserted through the nares; subsequent movement of the probe does not stimulate or irritate the airway mucosa because the probe is inside the catheter. Rotation of the probe tip at 1.25 Hz provides a 360° view of the upper airway, with motorized movement of the probe allowing images to be obtained from the nasopharynx to the laryngopharynx. The mean differences in upper airway dimensions between measurements obtained with this method and computed tomography were small (0.7 and 0.4 mm for anteroposterior and lateral diameters, respectively, with limits of agreement of –3.5 to 4.8 mm and –6.8 to 7.6 mm). The correlation coefficient for measurements of airway cross-sectional area using optical coherence versus computed tomography was 0.89. Measurements of airway compliance with application of CPAP, and images of the sites of upper airway closure in a sleeping patient with OSA, were also obtained. The authors conclude that this application of optical coherence tomography can provide quantitative measurements of upper airway size and shape with minimal invasiveness and few of the disadvantages of other imaging techniques, while also allowing study over prolonged periods of time, such as during wakefulness and sleep.
Because there is some evidence of genetic risk factors for sleep apnea, Schwab and coworkers (7) hypothesized that anatomic risk factors for OSA would demonstrate family aggregation. The authors performed volumetric (three-dimensional) magnetic resonance imaging of the upper airway in 55 probands with OSA and their siblings of the same sex, and 55 neighborhood control subjects and their siblings also of the same sex, all matched for age and ethnicity. The volumes of the lateral pharyngeal walls, tongue, and total upper airway soft tissue all showed significant levels of heritability. The degree of heritability was assessed as the percentage of total variance around the mean of the phenotype measure that was explained by systematic variance between families. Heritability was between 36 and 38% for these measures of upper airway soft tissue and was highly statistically significant (each p Obesity is associated with upper airway narrowing in humans and is a known risk factor for OSA. Because the Zucker rat is an established model of obesity, Brennick and colleagues (9) measured upper airway size in anesthetized and spontaneously breathing obese Zucker rats and lean littermate control rats using respiratory-gated magnetic resonance imaging. Noninvasive tissue tagging was also performed to provide an index of pharyngeal wall tissue strain. Obese Zucker rats had narrower upper airways compared with lean littermates, and showed smaller increases in airway size during inspiration. Despite these differences in airway size during breathing, lean and obese rats showed similar values of pharyngeal wall tissue strain. The authors suggest that obesity imposes a mechanical load on the upper airway that prevents a normal airway opening response to a given change in pharyngeal wall tissue strain in the obese rats. Overall, therefore, this study provides support for the concept that obesity, a major predictor of OSA, compromises upper airway size and function. NEUROMODULATION AND ADVANCES IN THE CONTROL OF BREATHING
Respiratory depression can occur in a variety of clinical circumstances, such as after pharmacological manipulation (e.g., opiate administration). Respiratory depression can also vary as a function of age (e.g., apnea of prematurity, and central and obstructive apneas in adults). Ampakines constitute a group of molecules that modulate the class of non-NMDA receptors that are activated by Seminal in vitro studies have identified a small region of the ventral lateral medulla termed the "pre–Bötzinger complex" as critical for the generation of basic respiratory rhythm in mammals (11). However, recent studies now implicate a second key site located in the parafacial respiratory group that overlaps the retrotrapezoid nucleus (12). Two articles discuss the evidence for which is the primary site of respiratory rhythm generation in mammals (13, 14), a significant topic given the fundamental importance of the genesis of breathing, and which provoked debate in the field (15). Specific interventions can also exploit the different pharmacological properties of pre–Bötzinger complex and parafacial respiratory group neurons to determine effects on their respiratory motor outputs. Although µ-opioid receptor agonists inhibit pre–Bötzinger complex neurons and slow respiratory rate, there is no effect on rhythmic activity of preinspiratory neurons of the parafacial respiratory group, with this rhythmic activity persisting in between the "skipped" diaphragm breaths during respiratory depression (11). Significantly, during opioid-induced respiratory slowing, rhythmic abdominal expiratory muscle activity as well as components of genioglossus muscle activity also persist in between the skipped diaphragm breaths, with this effect abolished by transections between the parafacial respiratory group and the pre–Bötzinger complex (16). Overall, these data provide novel evidence for dual networks for respiratory rhythm generation in mammals (inspiratory and expiratory) that are normally coupled (11, 17), and suggest that the neural drive modulating the diaphragm and components of genioglossus activity may arise from separate anatomic sources. Recent advances in clinical sleep-disordered breathing (SDB) are also discussed in a comprehensive review by Allan Pack (18). CENTRAL CONGENITAL HYPOVENTILATION SYNDROME Central congenital hypoventilation syndrome (CCHS) is characterized by autonomic nervous system disturbances and SDB. The gene for CCHS has been identified as a paired-like homeobox (PHOX)2B located on chromosome 4p12. Most cases of CCHS are heterozygous for the PHOX2B polyalanine repeat expansion mutation, with alternative mutations in PHOX2B in the other cases. Berry-Kravis and colleagues (19) characterized these nonpolyalanine repeat mutations in PHOX2B and compared the clinical phenotype of these cases of CCHS to those with the more common polyalanine expansion mutations. DNA from a total of 184 CCHS probands showed that 170 (92%) exhibited the polyalanine expansion mutations and 14 (8%) exhibited the nonpolyalanine expansion mutations, including missense, non-sense, and frameshift mutations. This latter group had over twice the rate of continuous ventilator dependence and much higher incidences of neural crest tumors and Hirschsprung disease (i.e., indicating a more severe clinical phenotype). Importantly, although this study showed that most of the nonpolyalanine expansion mutations occurred de novo, some were inherited and were from otherwise asymptomatic carriers. The authors emphasize that recurrence risk can therefore exist in families in which a CCHS proband has a nonpolyalanine expansion mutation, and that genetic screening of parents is important once such a mutation has been identified in a child. In addition, currently asymptomatic parents or siblings who carry this mutation in PHOX2B may also be at some risk for subsequent development of nocturnal hypoventilation or late-onset atypical CCHS. Although CCHS is typically identified in newborns, it can also present in adults. Antic and colleagues (20) describe a series of five cases (22–36 yr) with PHOX2B mutation–confirmed CCHS. These individuals survived to adulthood without manifesting the early respiratory failure associated with the typical CCHR phenotype, and did not require artificial ventilation until the time of diagnosis. All the cases exhibited the 25-repeat expansion in their mutated allele, the smallest expansion known to cause CCHS, and only exhibited subtle symptoms during childhood (e.g., an extraordinary ability to breath-hold for prolonged periods, and the occurrence of unexplained seizures). Given the results of the former study and the concerns regarding heritability (19), it is also relevant to note that three of the adult cases of this latter study (20) each had two offspring with CCHS. A further case report by Bachetti and coworkers (21) describes two unrelated patients with CCHS diagnosed by identification of the PHOX2B polyalanine expansion mutation. Magnetic resonance imaging in these patients, however, also showed evidence of pontine hypoplasia and a Chiari I malformation, respectively. Because the guidelines from the American Thoracic Society state that CCHS is diagnosed in the absence of an identifiable brainstem lesion (22), the authors comment that this criterion may be too restrictive. Indeed, the authors further comment that strict adherence to these guidelines led to the initial exclusion of a diagnosis of CCHS, as they assumed that the compromised breathing observed during sleep in these patients was because of the identified brainstem defects. This report highlights, however, the ultimate importance of the molecular analysis of the PHOX2B gene to definitively establish the diagnosis of CCHS. SDB AND DRIVING RISK Sleepiness plays a role in crashes of commercial vehicles. Pack and colleagues (23) evaluated the role of short sleep duration and sleep apnea on subjective sleepiness (Epworth Sleepiness Scale), objective sleepiness (sleep-onset latency), and neurobehavioral functioning (Divided Attention Driving Task) in 247 commercial drivers at higher risk for apnea and in 159 at lower risk. Shorter sleep duration was significantly associated with subjective sleepiness, objective sleepiness, and performance lapses, as well as poorer lane tracking, whereas increasing severity of sleep apnea was only associated with objective sleepiness. These data suggested that, among commercial drivers, both sleep deprivation and sleep apnea have the potential to impair the ability to safely operate a motor vehicle, but that sleep deprivation appears to pose a greater risk. However, because the effects of these factors on actual motor vehicle accident rates were not assessed, further work is required to determine whether commercial drivers should be screened for these sleep-related problems in an attempt to reduce motor vehicle accident rates. SDB AND BIOMARKERS OF CARDIOVASCULAR RISK Although an association between preeclamptic toxemia (PET) and SDB had been previously described, a potential link between SDB and cardiovascular risk in such patients had not been examined. Yinon and coworkers (24) performed sleep studies and evaluated endothelial function by assessing reactive hyperemia in 17 pregnant women with PET and 25 women with uncomplicated pregnancies. Patients with PET had a significantly higher respiratory disturbance index (18.4 ± 8.4 vs. 8.3 ± 1.3 per h of sleep, p < 0.05) and lower reactive hyperemia (p < 0.05). There was also a significant direct correlation between blood pressure, which was higher in the PET group, and respiratory disturbance index, and a significant inverse correlation between blood pressure and reactive hyperemia. The authors speculated that SDB may contribute to the functional abnormality of the blood vessels seen in females with PET that might contribute to their elevated blood pressure. OSA is associated with metabolic dysfunction that improves with treatment of OSA in adults, but it was not known whether this was true in children. In 45 children aged 6.9 ± 3.5 years (including 12 who were obese), Waters and colleagues (25) measured metabolic markers at the time of diagnostic polysomnography and at follow-up 1.3 ± 0.6 years later. There were no differences in metabolic markers between 32 children with and 13 without OSA on the initial study. However, compared with nonobese children, those who were obese had significantly higher insulin levels (106.1 ± 72.1 vs. 66.7 ± 37.6 pmol/L, p = 0.028), and significantly lower high-density lipoprotein cholesterol levels (1.3 ± 0.2 vs. 1.6 ± 0.4 nmol/L, p = 0.005). OSA resolved in 27 patients either spontaneously or in association with adenotonsillectomy, but persisted in 5 patients. At follow-up, there was a significant improvement in total cholesterol in those children whose OSA resolved (4.8 ± 0.8 to 4.7 ± 0.6 nmol/L, p = 0.005) and a trend for obese children with persisting OSA to have elevated insulin levels compared with obese children without OSA (p = 0.07). These data suggest that obesity is the major influence on metabolic dysfunction in children with OSA, but they also suggest that resolution of OSA may improve metabolic function.
Tumor necrosis factor (TNF)– Grebe and colleagues (27) measured vascular endothelial-dependent vasodilation by assessing flow-mediated dilation (FMD) of the brachial artery by ultrasound in 10 untreated patients with OSA and 10 control subjects without OSA before and after intravenous injection of the antioxidant vitamin C. Compared with control subjects, baseline FMD was significantly reduced in the patients with OSA. After intravenous injection of 0.5 g of vitamin C, FMD remained unchanged in the control subjects, but increased in patients with OSA. These results implicated oxidative stress in the pathogenesis of vascular endothelial dysfunction in OSA, and suggest that antioxidant therapy should be tested for the treatment of OSA-related cardiovascular disease. Taken together, the above-referenced articles suggest that, through intermittent hypoxia, OSA can provoke oxidative stress and elaboration of inflammatory mediators that have adverse effects on vascular responsiveness to endothelially mediated dilation. SDB AND CARDIOVASCULAR DISEASES
Cardiac Arrhythmias
Left Ventricular Hypertrophy
Heart Failure
Previous studies suggested that patients with heart failure and with OSA often do not complain of sleepiness, but comparisons with patients without heart failure were not performed. Therefore, Arzt and colleagues (31) compared sleepiness, assessed by the Epworth Sleepiness Scale, and sleep structure, assessed by polysomnography, between 155 patients with heart failure and 1,139 subjects from the Wisconsin Sleep Cohort classified according to their AHI (< 5, no OSA; 5–14, mild OSA; and Edematous patients with heart or renal failure have a higher prevalence of OSA than in the general population, but the reason for this is not known. One possibility is that fluid displacement into nuchal and peripharyngeal soft tissues while recumbent might contribute to narrowing and increased pharyngeal resistance (RPH), and predispose to pharyngeal collapse. To mimic the effects of rostral fluid displacement from the legs in recumbent edematous patients, Chiu and colleagues (32) displaced fluid from the legs by application of 40 mm Hg of lower body positive pressure via antishock trousers in 11 healthy nonobese subjects while simultaneously measuring neck circumference and RPH. Compared with a control period, application of lower body positive pressure for 5 minutes caused a significant reduction in leg fluid volume (p < 0.001) and significant increases in neck circumference (p = 0.004) and RPH (from 0.43 ± 0.10 to 0.87 ± 0.19 cm H2O/L/s, p < 0.001). These findings provide the first evidence that that rostral fluid displacement from the legs can increase RPH in healthy subjects. They imply that fluid displacement to the upper body while recumbent may predispose to pharyngeal obstruction during sleep, especially in fluid overload states, such as heart and renal failure, thereby predisposing to OSA. However, a significant limitation of this study was that subjects were studied while awake, so that the effect of fluid displacement on pharyngeal collapsibility during sleep was not determined. In patients with heart failure, central apneas are caused by a fall in PaCO2 and rise in pH below and above the threshold for apnea, respectively. Accordingly, Javaheri (33) tested the hypothesis that induction of metabolic acidosis by administration of acetazolamide, a carbonic anhydrase inhibitor, would alleviate CSA in patients with heart failure. Twelve male patients with stable systolic heart failure with CSA and an AHI of more than 15 events per hour of sleep were randomized to 6 nights of acetazolamide or placebo in a double-blind crossover protocol with a 2-week washout. Compared with placebo, acetazolamide reduced pH (7.43 vs. 7.36, p = 0.001), AHI (49 ± 28 vs. 23 ± 21, p = 0.004), and subjective perception of daytime sleepiness (p = 0.002). However, there was no improvement in left ventricular systolic function or pulmonary function. They concluded that short-term administration of acetazolamide can alleviate CSA and daytime sleepiness in patients with heart failure. However, because this study was of very short duration, and because long-term induction of metabolic acidosis has the potential to cause adverse effects in patients with heart failure, these findings do not constitute an indication for acetazolamide to treat CSA in patients with heart failure. OSA and CSA are common in heart failure, and may participate in its progression by exposing the heart to intermittent hypoxia, increased preload and afterload, sympathetic activation, and vascular endothelial dysfunction. Accordingly, treatment of these disorders in patients with heart failure may reverse such detrimental effects, and improve cardiovascular outcomes. Arzt and Bradley (34) provided a comprehensive review of the results of clinical trials in this area. They concluded that, although there is evidence that treating both OSA and CSA in patients with heart failure improves cardiovascular function, there is as yet no solid evidence that this leads to improved clinically important outcomes. Consequently, larger randomized trials with sufficient statistical power will be required to determine whether treating these sleep-related breathing disorders with interventions such as oxygen, CPAP, or other forms of positive airway pressure reduce morbidity and mortality.
Cardiac Pacing for OSA FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form January 9, 2007; accepted in final form January 9, 2007 REFERENCES
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1-adrenergic receptor mechanisms at the hypoglossal motor nucleus in modulating genioglossus muscle activity in rats. The rats were implanted with electrodes to record genioglossus and diaphragm activities across sleep–wake states. Microdialysis probes in the hypoglossal motor nucleus were used to perfuse artificial cerebrospinal fluid (control) and terazosin (
0.001) after adjusting for sex, ethnicity, age, visceral neck fat, and craniofacial dimensions (lateral and anteroposterior head measurements). Because Schwab and colleagues have previously demonstrated that increased volumes of these soft tissue structures pose significantly increased risk for OSA (
30 events/h) and 338 subjects without OSA (AHI < 5 events/h). Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (bigeminy, trigeminy, or quadrigeminy) were more common in subjects with OSA than in those without OSA (4.8 vs. 0.9%, p = 0.003, for atrial fibrillation; 5.3 vs. 1.2%, p = 0.004, for nonsustained ventricular tachycardia; and 25.0 vs. 14.5%, p = 0.002, for complex ventricular ectopy). The authors concluded that individuals with severe OSA have a significantly higher prevalence of cardiac arrhythmias than those without OSA after adjustment for potential confounders. These findings emphasize the need for randomized trials to determine whether such arrhythmias are amenable to therapy for OSA. 
B–dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824–830.
