Approach

The goal of treatment for all subtypes of central sleep apnea (CSA) syndrome is to restore a normal breathing pattern and to improve symptoms and sleep patterns. Treatment typically consists of a combination of positive pressure ventilation, supplemental oxygen, and addressing the underlying or associated condition, if any. However, the evidence for these therapeutic approaches is largely confined to observational data or small, short-term randomized trials with surrogate endpoints. Few large, randomized controlled trials are available in patients with predominant CSA syndromes. Furthermore, data on whether these interventions improve survival vary. In general, as with all patients with sleep-disordered breathing, patients with CSA syndromes who are visibly somnolent, report excessive daytime sleepiness, and/or have an elevated Epworth Sleepiness Scale score should be counseled about the dangers of driving or operating heavy equipment while sleepy and advised to avoid doing so.

Medical disorders without Cheyne-Stokes breathing (CSB)

The goals of treating CSA due to a medical disorder without CSB are to improve sleep and daytime symptoms and to normalize the breathing patterns. The following recommendations are based on current limited literature in the management of CSA in patients with brainstem lesions of vascular, neoplastic, degenerative, demyelinating, or traumatic origin. When CSA is due to stroke, an initial trial of continuous positive airway pressure (CPAP) is recommended, followed by a trial of adaptive servoventilation (ASV) if CPAP is not effective. In cases associated with end-stage renal disease, CPAP should be tried first, followed by a trial of oxygen at 2 to 4 liters per minute via a nasal cannula if CPAP proves poorly effective. If oxygen is not effective, there may be some benefit to switching the dialysis buffer to bicarbonate instead of acetate or in changing from daytime to nocturnal hemodialysis.[45]

ASV is contraindicated in patients with symptomatic heart failure with ejection fraction ≤45% even though it effectively reduces the apnea-hypopnea index (AHI), based on data that show no improvement in cardiovascular outcomes and increased mortality.​​​​[22][39][46]

Primary (idiopathic) CSA

The major goal of treating primary (idiopathic) CSA syndromes is to improve symptoms and to normalize sleep and breathing parameters. However, because the long-term consequences or complications of primary CSA are not known, symptomatic improvement is probably most important.

The condition is unusual, and there is a paucity of published trials to provide strong evidence for a preferred treatment modality. After polysomnographic diagnosis, a trial of CPAP may be used. This leads to normalization of the AHI in some patients.[47][48] However, ASV has been more consistent in controlling sleep-disordered breathing in these patients compared with CPAP.[49] Although ASV appears to more reliably control CSA in patients without CSB (idiopathic or due to medical conditions), some guidelines require proof that CPAP is ineffective before trials of ASV are recommended.[45]

If CPAP and ASV prove ineffective, limited data support an off-label trial of acetazolamide, zolpidem, or triazolam in CSA treatment.[50][51][52][53] Due to limited available evidence and the potential of side effects, pharmacologic intervention in primary CSA should be individualized until further studies are available.[45]

Central sleep apnea with Cheyne-Stokes breathing

There is no widely accepted treatment modality or approach for CSA and CSA-CSB in patients with congestive heart failure (CHF). Although several interventions have been used, none has demonstrated enough efficacy or safety today to become broadly accepted.

Abnormal breathing and sleep patterns may resolve once management of the underlying condition (e.g., CHF, renal failure, stroke) is optimized.[54] Optimization of cardiovascular pharmacotherapy (guideline-directed medical therapy) should be counted among the first interventions in the management of CHF with reduced ejection fraction. The use of beta-blockers, ACE inhibitors, angiotensin-II receptor antagonists, aldosterone antagonists, and diuretics have salutary effects in the hemodynamics, with potential benefits in sleep-disordered breathing.

If positive airway pressure therapy is indicated because of sleep symptoms or to improve hemodynamics, continuous positive airway pressure (CPAP) titrated to eliminate respiratory events is the next step.[45] CPAP delivers a constant preset pressure to the airways. It is ideally initiated after expert mask fitting and patient education including familiarization with the procedures and equipment and is best begun during attended polysomnography, with pressure set at 5 cm H₂O. Pressure is then titrated up, ideally while the patient is in nonrapid eye movement supine sleep, in an attempt to normalize the AHI and sleep architecture.​ 

The use of positive airway pressure devices for CSA in patients with CHF with predominant reduced ejection fraction must be approached with caution.

Based on the 2022 report of the American College of Cardiology/American Heart Association guideline for the management of heart failure (HF), implementation of CPAP is recommended for patients with HF and central sleep apnea, based on improvements in sleep quality and nocturnal oxygenation, although it has not been shown to affect survival.[22] However, in a post-hoc analysis, CPAP has been shown to decrease the combined mortality-cardiac transplantation rate in patients with CHF and CSA-CSB who comply with therapy.​[43]​​ For patients with CHF with reduced ejection fraction and sleep-disordered breathing, meta-analyses found that positive airway pressure therapy is associated with improvements in left ventricular ejection fraction and blood pressure and a moderate decrease in brain natriuretic peptide (BNP).​[22]

Unlike CPAP, ASV is detrimental for patients with CHF with reduced ejection fraction.[22] Evidence shows ASV treatment is associated with increased mortality rates.[22]​ The American College of Cardiology/American Heart Association guidelines for the treatment of CHF recommend against its use in patients with CSA and New York Heart Association class II-IV reduced ejection fraction CHF, rating it as harmful.[22] Results from the SERVE-HF trial, which assessed the effects of treatment of CSA with ASV on mortality and morbidity in patients with symptomatic chronic heart failure (New York Heart Association class II-IV) with reduced ejection fraction (left ventricular ejection fraction ≤45%), showed an increased risk of cardiovascular mortality for those treated with ASV in comparison with those who received the best medical care alone.[46] A post-hoc analysis of the SERVE-HF trial using multistate modeling found that the increased risk of cardiovascular death appears to be greatest in those with pure CSA with more severe ventricular dysfunction, presumably related to sudden cardiac death. The patients with severe left ventricular dysfunction at baseline and without an implantable cardioverter defibrillator were particularly at risk of cardiovascular death.[55] Results from the cardiovascular improvements with minute ventilation-targeted ASV therapy in heart failure trial (CAT-HF) found ASV did not improve 6-month cardiovascular outcomes compared with best medical care alone in patients with CHF, although a pre-specified subgroup analysis showed ASV had a positive effect in patients with CHF with preserved ejection fraction.[56] Additional studies are needed to accurately identify the long-term impact of ASV in patients who have CHF-related CSA with varied left ventricular ejection fractions, as well as in those who have preserved ejection fraction.[39][46]​​​​[56]

A meta-analysis evaluating positive pressure therapy (ASV or CPAP) at up to 31 months has been uncertain regarding impact on all cause mortality.[57] In addition, there were no benefits in the risk of cardiac-related mortality and rehospitalization. However, there was some indication of an improvement in quality of life for heart failure patients with CSA. Therefore, if therapy is considered due to the patient's sleep symptoms or hemodynamic status, CPAP implementation for CSA in these patients has been shown to reduce the frequency of respiratory events, improve hemodynamics and exercise tolerance.​​​

Supplemental nocturnal oxygen attempts to significantly reduce upward modulation of the ventilatory response by hypoxic drive.[45] Because patients with CSA typically have high ventilatory drives even at normal oxygen saturations, an increase in mean SaO₂ above normal (goal mean SaO₂ ≥95%) should be attempted. Supplementary nocturnal oxygen therapy is typically supplied at 2 to 4 or 5 liters through a nasal cannula, and is usually attempted if CPAP is not available or is contraindicated. Nocturnal oxygen improves oxygen saturation index and ejection fraction, and reduces the number of respiratory events without clinically significant adverse effects. At higher flow rates, nasal dryness may be problematic, and use of nasal cups, humidification, or a full face mask may alleviate this problem. Can also be helpful even in normoxic patients, who may not meet usual criteria for supplemental domiciliary oxygen. Whether or not targeting nocturnal hypoxemia is associated with beneficial effects on mortality remains to be determined.

Another option is bilevel positive airway pressure with spontaneous/timed back up rate. This is usually delivered by a bilevel positive airway pressure device, whereby one sets the inspiratory and expiratory pressure supports, as well as the spontaneous-timed back-up ventilatory rate. Bilevel positive pressure ventilation with back up rate has been shown to improve apnea-hypopnea index (AHI), but no long-term data are available.​[58]​ Initiation follows expert mask fitting and patient education including familiarization with the procedures and equipment. Typical initial settings are: end-expiratory pressure 5 cm H₂O, inspiratory pressure 9-10 cm H₂O, and back-up rate 12 to 14. Pressures are then adjusted in an attempt to normalize the AHI and sleep architecture, ideally while the patient is in nonrapid eye movement supine sleep, when CSA events would be expected to be most severe.​

Cardiac resynchronization therapy has been shown to reduce Cheyne-Stokes breathing in some CSA patients with congestive heart failure (CHF).[59] There are limited data that show a reduction in apnea-hypopnea index with the use of acetazolamide and theophylline in patients with CHF and CSA syndromes.​​[60]​​[61][62] These therapies may be considered if, after optimization of medical therapy, positive airway pressure therapy is not tolerated and if accompanied by close clinical follow-up.​​​[45]

High-altitude periodic breathing

High-altitude periodic breathing causes sleep disruption, daytime sleepiness, fatigue, and impaired performance. Effective treatment improves some or all of the symptoms. The relationship between high-altitude periodic breathing and acute mountain sickness is not established, but they may coexist. However, treating high-altitude periodic breathing may improve symptoms of acute mountain sickness.

The most effective treatment is to return the patient to a lower altitude or to sea level. While awaiting transport, supplemental oxygen may be of benefit.

Available data supporting the use of acetazolamide are limited. Commonly used in preventing acute mountain sickness, acetazolamide causes metabolic acidosis by increasing bicarbonate secretion from the kidneys. This increases ventilation and arterial oxygenation, facilitating acclimatization to high altitude in healthy individuals.[63] At high altitude, acetazolamide has also shown to improve CSA by decreasing the percentage of central periodic breathing and increasing nocturnal oxygenation in healthy individuals.

Although less effective than in healthy individuals, acetazolamide has also been shown to decrease CSA in obstructive sleep apnea (OSA) patients at high altitude. Based on data from randomized trials, it seems advisable for patients with OSA to use CPAP treatment (e.g., autoCPAP) in combination with acetazolamide to adequately control obstructive and central apneas/hypopneas during an altitude sojourn.[64][65] 

Further supplemental oxygen implemented through CPAP might be advisable for some patients. The indication has to be assessed individually according to recommendations for the underlying disease.

See High altitude related illness (Primary prevention).

Medication or substance misuse

Symptoms improve when treatment is effective. The long-term complications directly attributable to CSA related to a drug are not established.

The approach to treatment should first involve removal or revision of the opioid or other candidate drug dose. If this is ineffective or impractical, response to a positive airway pressure device is similar to that with other forms of CSA. Some reports indicate a less than satisfactory response to CPAP, and there are mixed data indicating a positive response to ASV.[66][67][68][69][70] If opioid-induced alveolar hypoventilation is suspected, a trial of bilevel positive airway pressure ventilation (BPAP) to maintain a minute ventilation should be considered first.[71]

Treatment-emergent CSA

By definition, patients have persistent or emergent CSAs while on positive airway pressure, associated with fragmented sleep and possible intolerance to CPAP treatment. Although most treatment-emergent CSA patients tend to improve with long-term CPAP use, up to 30% will remain with persistent CSA; these patients may benefit from noninvasive ventilation.[72]

In comparison to CPAP and bilevel positive airway pressure, ASV treatment has been shown to have not only a significantly greater decrease of the AHI in all positions and stages of sleep, but also a lower residual arousal index, and a higher percentage of REM sleep.[66][73] This beneficial effect should not be attributable to patients with occult CHF, as ASV has been proven to be an effective treatment for patients with normal B-type natriuretic peptide, excluding possible confounding of CSA-CSB cases.[74]

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