Juxtaposed in the spectrum of sleep disordered breathing is upper airway resistance syndrome (UARS) and obstructive sleep apnea/hypopnea syndrome (OSA). UARS and OSA are integrated together by one important perturbation – increased respiratory effort. Changes from normal respiratory physiology and ventilation control during sleep as compared with wakefulness include increased upper airway inspiratory resistance. Respiratory effort increases, in part, as a function of increasing upper airway resistance. Whereas, UARS is not associated with hypoxia, both UARS and OSA are associated with arousals, often referred to as micro-arousals when shorter than 15 seconds. Otherwise, it is scored as an awakening. Micro-arousals are accompanied by a rapid increase in blood pressure and heart rate evoked by an elevation in sympathetic drive and decrease in parasympathetic tone. In the long term, persistent and chronic micro-arousals may be associated with vascular endothelial dysfunction commonly seen in metabolic syndrome, and future risk for cardio-vascular disease.
UARS is often termed respiratory effort-related arousals (RERA). RERA events are determined by standard polysomnography, and are integrated into the total number of sleep disordered breathing events. The convention is to report the sum of UARS and OSA as the respiratory disturbance index (RDI). Thus, UARS and OSA can be viewed as comorbid conditions. Collectively, both UARS and OSA are characterized by increased respiratory effort evoked by upper airway resistance followed by micro-arousals that are deviations from the highly structured architecture of normal sleep. (In the absence of increased respiratory effort, the arousal is scored as central apnea.)
In addition to a risk of vascular disease, metabolic consequences attend the comorbidity of UARS and OSA. These include the role played by glucocorticoid and adenosine.
The result of persistent arousals from normal sleep architecture is fragmented sleep and sleep distress. The stress of persistent arousals in the setting of chronic sleep deprivation are most disturbing to synchronized, high amplitude, slow-wave sleep. It is well known that stress raises the serum levels of the stress hormone, glucocorticoid, via hyperfunction of the hypothalamic-pituitary-adrenocortical axis (HPA axis). One of the fundamentals of sleep medicine is that endocrinopathy, such as frequent cortisol elevations during sleep, increases the prevalence of sleep disordered breathing. High levels of glucocorticoids make it harder to transition into slow-wave non-REM sleep.
During normal, free-running EEG sleep patterns, glucocorticoid release is low. Near the end of a quiet night of restorative sleep, glucocorticoid levels begin to rise in anticipation of wakefulness. On the other hand, under conditions of sleep distress in the setting of increased respiratory effort seen in UARS and OSA, micro-arousals cause levels of glucocorticoid to cycle up repeatedly through the night causing hypersynchronous non-REM activity and “alpha stage intrusions” leading to fragmented sleep.
The brain’s response to persistent, stressful fragmented sleep is the secretion of corticotrophin-releasing hormone (CRH) into the portal circulation and initiating the cascade of hormonal events of HPA axis hyperfunction. CRH is a hypothalamic excitatory hormone causing the secretion of the hormone ACTH from the anterior lobe of the pituitary. Interestingly, in animal studies, stereotactic neurotoxic lesions of the paraventricular nucleus of the hypothalamus reduces ACTH secretion in response to experimental stress. In turn, a corticotrophin-release inhibitory factor (CIF) has been characterized (though not yet isolated) that inhibits ACTH synthesis and secretion (Figure 1).
This putative endogenous agent has been called the delta sleep factor that tends to increase the percentage of time devoted to normal slow-wave EEG patterns. Therefore, it appears that the same chemical messenger that improves transition to Stage 3 synchronized sleep is similar to a messenger that decreases glucocorticoid release. Presumably, the absence of delta sleep factor occurs in UARS and OSA since both are associated with multiple repeating micro-arousals that leverage the basal HPA axis.
Glucocorticoids were one of the first signaling molecules to be identified as playing a role in the coordination of circadian rhythms. The 2 clusters of suprachiasmatic nuclei (SCN), responsible for circadian oscillations, send direct projections to the paraventricular nucleus of the hypothalamus that release CRH. Presumably, these direct axonal projections to the paraventricular nucleus are excitatory causing release of CRH. Interestingly, in laboratory experiments, adrenalectomy alters the light-induced daily geophysical entrainment involved in circadian control. The process of entrainment is at the core of sleep problems that result from jet lag and shift work. Thus, it appears that the SCN, in part, regulates the cyclical secretion of glucocorticoids. Add to that the microarousals and “alpha stage intrusions” of fragmented sleep, and the consequence is the double jeopardy of glucocorticoid-induced sleep disruption.
Part 2 that follows in the next edition will explain how adenosine produced out of the process of intermediary metabolism is involved in the comorbidity of UARS and OSA.
Brian D. Fuselier, DDS, is a member of the International Association for the Study of Pain, and the American Pain Society.
Barry A. Loughner, DDS, MS, PhD is a member of the International Association for the Study of Pain, the American Pain Society, the American Dental Association, and the Ethics Committee of the American Association for the Study of Headache.
Dr. Fuselier and Dr. Loughner are actively practicing at Central Florida Oral and Maxillofacial Surgery, a unique service with both oral surgeons and facial pain specialists practicing together. For more information visit www.cforalsurgery.com