Adaptive responses using obstructive sleep apnea as the paradigm.

For practicing clinicians, obstructive sleep apnea (OSA) represents an excellent illustration of how understanding adaptive physiological principles are required for optimal patient care. Clinically important OSA is estimated to affect roughly 13% of North American men, 6% of North American women, and 2% of children based on current criteria (11). The disease is characterized by repetitive collapse of the pharyngeal airway, which occurs during sleep, resulting in hypoxemia, hypercapnia, and sleep fragmentation, leading to adverse metabolic, neurocognitive, and cardiovascular consequences. Nasal continuous positive airway pressure (CPAP) is the treatment of choice for OSA in adults, but long-term adherence is unsuccessful in 50% of patients (8), leading to a requirement for further research to develop new therapies. Traditionally OSA was considered a result of abnormalities in craniofacial structure and/or parapharyngeal soft tissues, which rendered the airway collapsible (8). Recently, it has become increasingly recognized that OSA is a multifactorial condition where several physiological determinants of airway patency, including neuromuscular activation, arousal threshold, and ventilatory control stability (8), are abnormal in OSA and contribute to differing degrees in each patient to propagate airway collapse. This concept has led to a personalized medicine approach being developed, whereby OSA patients might be treated in an individualized manner based on an underlying physiological mechanism (3, 9). However, the question remains whether these traits, which are abnormal in OSA patients, are inherent and contribute to the onset of disease, or whether they are acquired as an adaptation to OSA. Then, if they are acquired, are they adaptive or maladaptive? At sleep onset, excitatory drives to upper airway dilator muscles associated with wakefulness are abruptly lost, and protective reflexes are dramatically blunted, yielding collapse of the vulnerable airway (6). During obstructed breathing, the ability to recruit upper airway dilator muscle activity is highly dependent on responsiveness to negative (subatmospheric) intrapharyngeal pressure and carbon dioxide. Both are respiratory stimuli that activate pharyngeal dilator muscles, particularly when the stimuli are provided in combination (8,6). Thus the arousal threshold becomes an important factor in determining whether apnea will occur. Patients with a high arousal threshold (hard to wake up) allow for the accumulation of negative intrapharyngeal pressure and CO2 during stable sleep, thus permitting sufficient neuromuscular compensation to maintain airway patency. By contrast, patients with a low arousal threshold (wake up easily) are at risk for repetitive apnea in part due to inadequate tolerance of sufficient respiratory stimuli to activate pharyngeal dilator muscles. Unstable ventilatory control (high loop gain) also has been implicated in OSA (15), whereby fluctuations in output from the central pattern generator in the brain stem can lead to upper airway collapse when output to the upper airway dilator muscles (and diaphragm) is at its nadir.