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INVITED EDITORIAL
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey
IN THEORY, obstructive apneas can be terminated either by arousal or by increases in chemical drive that excite the upper airway dilating muscles (1). However, the still-prevalent view, which Younes et al. (13) test in their study in the Journal of Applied Physiology, is that obstructive sleep apneas are terminated only by arousals (8). This view is still so dominant that any increase in airflow seen during a period of obstruction is considered by some to be a sign of arousal. This view has been challenged by Younes and by others (7, 12). Younes has shown previously instances of the reestablishment of flow during a period of obstruction without any electroencephalographic evidence of arousal (12).
Younes et al. (13) describe quite ingenious experiments in 21 patients with severe sleep apnea that separate airway reopening due to increased chemical drive from arousal. A major difficulty in these experiments is that increasing chemical drive incites not just increases in the activity of the upper airway muscles but also arousal and ventilation. The patients initially breathed room air with sufficient continuous positive airway pressure (CPAP) so that normal blood gas tensions were preserved while the EEG was monitored to detect arousal. The level of CPAP was then rapidly "dialed down," i.e., reduced until complete obstruction occurred or, if it did not, to 1 cmH2O, which produced marked hypopneas. Then the process was repeated, substituting for room air different gas mixtures either enriched with CO2 and/or deficient in oxygen. An increase in airflow during dial down was used to signal airway reopening, while EEG changes were used to detect arousals. Two indexes were developed: a threshold for effective recruitment (TER) and a threshold for arousal (TA), both of which were expressed as a percentage of the baseline ventilation, allowing them to be compared. In 12 of 21 patients, airway reopening occurred before arousal even when the EEG was examined by spectral analysis, and the possibility of subcortical (autonomic) arousals was explored by an analysis of heart rate. A complication was that thresholds for arousal and for airway reopening by increased chemical drive were often quite close together but were unrelated. It is also interesting that once the upper airway reopened, maximal flow was achieved with very little increase in chemical drive, suggesting a very steep response.
These results lead Younes et al. to conclude that arousal is not needed for airway reopening. Perhaps even more important, by integrating data from this study and previous studies (12–14), Younes et al. develop a quite reasonable explanation for repetitive obstructive apneas. Previous studies had demonstrated that arousal destabilizes breathing and aggravates sleep apnea because it leads to overshoots and subsequent undershoots in blood gases and ventilation (12). Circulatory delays and high loop gain may perpetuate obstructive sleep apnea by causing ventilation to reach the arousal threshold even though the airways are already open (7). Increased chemosensitivity, which occurs in many patients with obstructive sleep apnea, would aggravate overshoots and undershoots during arousal (3, 7, 14). The same features that Younes believes perpetuates obstructive apneas also tend to produce recurring central apneas when the upper airway is more rigid, and are likely to be an important cause of the occurrence of both kinds of apnea in the same subject (3). This does not mean that arousal is an essential feature for either recurring central or obstructive apneas, but rather that arousal helps destabilize breathing. Theoretically at least, recurrent obstructive apneas might occur because of enhanced chemosensitivity and circulatory delays even if arousal does not occur, as when the arousal threshold is very high (3, 7).
The idea that underlies the study of Younes et al. (13) and many others is that airway patency depends on a balance between two opposing forces: the net dilating effect of increased chemical drive on upper airway muscles versus the collapsing tendency resulting from the increasing flow caused by contraction of the thoracic pump muscles (1, 7). Enhanced chemical drive augments both opening and collapsing forces. In order for the airways to open in the absence of arousal, the mechanical action of upper airway muscles at some level of chemical drive must exceed that of the pump muscles. The appropriate experimental studies in humans to test how this occurs have not yet been done.
The measurements made by Younes et al. are approximations lumping together in a single value, such as the threshold of effective recruitment and the arousal threshold, a quite complex chain of events (13). Airflow through the twisted and convoluted passages of the upper airway produces dynamic changes in airway pressures due to interchanges between static and kinetic energy (4, 5). The Bernoulli effect, suggested as a mechanism for snoring, may also contribute to airway collapse (5). Complicated models both physical and/or mathematical have been proposed to predict the topography of pressures in the upper airways in part to help decide what reparative surgical procedures should be carried out to prevent airway obstruction (6).
Granted that we have much to learn about what arousal really is, how it occurs, and why its threshold varies during sleep, Younes et al. (13) have found a significant relationship between arousal threshold and ventilatory chemosensitivity, suggesting that arousal depends on derivatives of ventilation like respiratory pressures. On the other hand, there was no relation between the level of ventilation produced by changes in chemical drives and the drive changes needed for airway reopening or widening (13). This is not surprising. The relation between airflow into the lungs and upper airway pressures depends on input not just from chemoreceptors but also from mechanoreceptors and other neural drives like the drive occurring with arousal (1–3).
Multiple muscles in the pharynx and larynx affect airway diameter; some widen but some also constrict the airway. The strap muscles of the neck by moving the hyoid can widen the upper airways, and their effectiveness varies with lung volume (10). However, the chemosensitivity of only a handful of upper airway muscles have been examined in humans by recording their EMG. It is clear that the responses of the various upper air muscles vary not just in terms of the changes in electrical activity as chemical drive varies, but also in threshold levels of blood gas tensions needed for activation (1, 7). They also respond differently to pressure and thermal stimuli (2, 12). It is likely that the relationships between muscle electrical activity and mechanical actions also vary considerably among muscles (9). The net dilating effect of increased chemical drive may not be linearly related to chemical drives and may differ among patients not just in steepness of response but even in shape.
It may take a long time before this can all be worked out. But one need not know the depth of all its craters to predict the phases of the moon. Luckily, like astronomers, sleep scientists need not know everything to make accurate predictions.
What the study of Younes et al. (13) tells us is that there are different ways in which recurrent obstructed apneas occur, but more importantly, the relationships between these different factors are understandable even if precise predictions cannot as yet be made. These insights compel us to take a fresh look at the treatment of obstructive apneas.
FOOTNOTES
Address for reprint requests and other correspondence: N. S. Cherniack, Dept. of Medicine, UMDNJ-NJMS, Newark, NJ (e-mail: Cherniac{at}umdnj.edu)
REFERENCES
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