Idiopathic CSA
There are limited data on the pathophysiology and prevalence of idiopathic CSA. In most cases it is hypocapnic CSA, which occurs after an arousal from sleep causing hyperventilation that causes hypocapnia below the apnea threshold similar to CSA-HAPB. Therapeutic options based on addressing underlying pathophysiology include increasing CO2 by inhalation or addition of dead space. Additional therapeutic options to reduce the arousals and CSAs include hypnotics, such as zolpidem and acetazolamide, but these should be administered only with close clinical monitoring. If symptoms continue, CPAP or ASV may be trialed; however, limited clinical evidence of efficacy exists.15
For patients with moderate-to-severe CSA, an additional treatment option includes an implantable device (eg, Zoll remede¯), which stimulates the phrenic nerve to move the diaphragm and restore normal breathing. This device is not indicated for those with OSA. Based on data submitted to the US Food and Drug Administration, AHI is reduced by ≥ 50% in 51% of patients with the implanted device and by 11% in patients without the device. Five-year follow-up data show sustained improvements.34
Hypercapnic CSA
CSA due to a medication or substance requires the following criteria: (1) the patient is taking an opioid or other respiratory depressant; (2) the patient reports sleepiness, awakening with shortness of breath, snoring, witnessed apneas, or insomnia (difficulty initiating or maintaining sleep, frequent awakenings, or nonrestorative sleep); (3) PSG reveals ≥ 5 CSAs and/or central hypopneas per hour of sleep; the number of CSAs and/or central hypopneas is > 50% of the total number of apneas and hypopneas; and there is no evidence of CSB; and (4) the disorder is not better explained by another current sleep disorder.8
Drugs that affect the respiratory centers, such as opiates and opioids, γ aminobutyric acid (GABA) type A and B receptor agonists, and P2Y(12) receptor antagonists such as ticagrelor, may result in alterations in ventilatory drive in the central nervous system respiratory centers, resulting in CSA.
Opioids are prescribed either for chronic pain or to treat opiate addiction with methadone, resulting in about one-third of chronic opioid users having some form of CSA.35 CSA may be seen after opioids have been used for at least 2 months. A dose-dependent effect exists with high doses of opioids, typically resulting in hypoventilation, hypercapnia, and hypoxemia with ataxic or erratic breathing and a periodic breathing pattern similar to those described in CSA-HAPB or idiopathic CSA. About 14% to 60% of methadone patients also demonstrate CSA or ataxic breathing.35,36
Benzodiazepines (GABA-A receptor agonists) and baclofen (a GABA-B receptor agonist) depress central ventilatory drive, blunt the response to hypoxia and hypercapnia, leading to CSAs, and increase risk for OSA by increasing upper airway obstruction through reduction in tone. Use of these medications with antidepressants or opioids further exacerbates this response.
Unlike the other medications previously described, ticagrelor, a first-line dual antiplatelet therapy medication indicated for acute coronary syndrome treatment, actually increases the activity of the respiratory centers but may result in CSA.
First-line treatment, if possible, is reduction in medication dose or complete withdrawal. Additional treatment options include PAP therapies: CPAP, BiPAP, ASV, and oxygen therapy with or without PAP.37,38 The literature has demonstrated that for the treatment of opioid-associated CSA, ASV (in cases of normocapnia) and noninvasive ventilation (NIV)/BiPAP (in cases with hypercapnia or REM sleep hypoventilation) are superior treatment options when compared with conventional CPAP for elimination of respiratory events. CPAP with oxygen therapy and BiPAP with oxygen therapy are more effective than CPAP alone in reducing respiratory events. However, concerns remain that as with CSA in HF, CSA in chronic opioid users may serve as a physiologic protective mechanism to prevent further clinical injury from opioids. Similarly, as in the use of ASV in the SERVE-HF trial, focusing on elimination of respiratory events may prove detrimental. More studies are needed to determine whether reducing the number of CSA events in chronic opioid users is clinically beneficial when other health outcomes, such as cardiovascular, neurocognitive, hospital/intensive care unit admissions, and mortality risks are examined.