Sleep respiratory function is driven by the bulbar respiratory center, which reacts to metabolic, mechanic, and behavioral influences. Metabolic regulation is exerted by changes in PO₂ and PCO₂: Increased PCO₂ stimulates the bulbar center, whereas a critical reduction in PCO₂ inhibits it. Ventilation drive is also increased with decreased levels of PO₂.

Mechanical (autonomic) regulation is under the control of pulmonary vagal receptors and can, if stimulated, give rise to reflex hyperventilation. Behavioral regulation of breathing is typical during the awake state. Behavioral regulation reacts to changing patterns of breathing such as seen during talking or with exercise. Ventilation will respond to behavioral inputs only during wake, not during nonrapid eye movement (NREM) sleep. It is thought that the reason for this is that the receptors for behavior regulation are in the forebrain and are not active during NREM sleep (4). PCO₂ during sleep decreases temporarily to below the critical level that is necessary to keep the respiratory rhythm normal.

There are many causes for loss of central respiratory impulse during sleep. Metabolic control and neuromuscular failure may cause chronic alveolar hypoventilation syndrome that worsens during sleep when the stimulating effect of wakefulness is absent (4, 5). CSA may also be caused by a transient instability of the respiratory drive that is otherwise undamaged: When the stimulating effect of wakefulness (neural wakefulness impulse) on respiration is lacking, then the apneic episode begins and continues until the PCO₂ critical level is reached (2).

Sleep affects respiration primarily at sleep onset when PCO₂ oscillates around the hypocapnic threshold (6, 7). Thus, CSA occurs with hypocapnia, and it ceases with arousal and hyperventilation. Subsequently recurring hypocapnia leads to a new apneic episode when sleep is resumed (8). Posthyperventilation CSA is less common during rapid eye movement (REM) sleep (9, 10).

Several physiologic and pathologic factors increase the risk of CSA, including age, sex, and many medical conditions. The threshold for hypocapnic CSA is higher in males, and CSA is rare in premenopausal women (11). Disorders such as thyroid dysfunction, cerebrovascular disease, acromegaly, renal failure, congestive heart failure (CHF), and atrial fibrillation may increase susceptibility to the development of CSA in older patients (12, 13).

CSA comprises 40% of apneas that develop following a cerebrovascular accident (CVA). The brainstem is the primary center for ventilation control, so any damage occurring there or to the medullary area from a CVA could impact regular respiration during sleep (14).

Over the last decade, there has been a dramatic change in the way chronic pain has been managed. The American Academy of Pain Medicine (AAPM) and the American Pain Society issued a joint position statement in 1997 stating, “It is now accepted by practitioners of the specialty of pain medicine that respiratory depression induced by opioids tends to be a short-lived phenomenon, generally occurs only in the opioid-naive patient, and is antagonized by pain. Therefore, withholding the appropriate use of opioids from a patient who is experiencing pain on the basis of respiratory concerns is unwarranted” (15). Ever since this statement was made, there have been multiple studies demonstrating an association of opioids with sleep apnea. Opioid use for pain management has increased, resulting in a rise in opioid-associated morbidity and mortality. The AAPM updated its statement on the Use of Opioids for the Treatment of Chronic Pain (15). Position 3 of that statement indicates: “Physicians should be sensitive to and seek to minimize the risks of addiction, respiratory depression and other adverse effects, tolerance and diversion” (15). The statement cautions titration of opioid medications in patients with underlying diagnoses such as sleep apnea (specifically CSA) or end-stage respiratory disease due to the increased risk of cardiorespiratory events. CSA occurs in 30% of patients undergoing stable methadone (opioid) maintenance treatment (15). The concern is that some patients present with CSA without any apparent risk factors. In these cases of “idiopathic” CSA, increased chemoresponsiveness or sleep state instability could be responsible for the irregularity in breathing patterns. Occasionally, these patients may have a theretofore undiagnosed metabolic or cardiac disorder (16, 17). Although CAs are commonly observed during initial polysomnography (PSG), they may be absent initially and appear during continuous positive airway pressure (CPAP) titration and present as treatment-emergent CSA. Central events that persisted with the use of CPAP or bilevel devices required more advanced therapy such as adaptive servo-ventilation (ASV) (18).