Central sleep apnea

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

without Cheyne-Stokes breathing: due to medical disorder

1st line – positive airway pressure: continuous positive airway pressure or adaptive servoventilation

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1st line –

positive airway pressure: continuous positive airway pressure or adaptive servoventilation

The goals of treating CSA without Cheyne-Stokes breathing that is due to a medical disorder or neurologic condition are to improve sleep and daytime symptoms and to normalize the breathing patterns.

Note that although adaptive servoventilation (ASV) appears to control CSA more reliably in these patients, some guidelines require proof that continuous positive airway pressure (CPAP) is ineffective before trials of ASV are recommended.

When CSA is due to stroke, an initial trial of CPAP is recommended, followed by a trial of 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.

CPAP delivers a constant preset pressure to the airways, and leads to normalization of the apnea-hypopnea index (AHI) in some patients.

ASV evaluates the patient's ventilatory patterns, and delivers variable pressure support and ventilatory rate support according to proprietary algorithms in order to reduce hypoventilation and hyperventilatory overshoot.

Both are ideally initiated after expert mask fitting and patient education including familiarization with the procedures and equipment.

Best begun during attended polysomnography, with pressure set at 5 cm H₂O (for CPAP) or 4 cm H₂O (for ASV).

In the case of CPAP, 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.

In the case of ASV, depending upon the device used, most often the rate and inspiratory pressure are automatically adjusted. End-expiratory pressure is then titrated up, to eliminate obstructive events, normalize breathing, and improve sleep architecture.

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

2nd line – supplemental oxygen

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2nd line –

supplemental oxygen

If adaptive servoventilation (ASV) and continuous positive airway pressure (CPAP) prove ineffective, supplemental oxygen provided through a nasal cannula at 2 to 4 L/minute has been shown to decrease central apnea-hypopnea index (AHI) in a small series, but is also not uniformly successful.

Supplemental oxygen attempts to significantly reduce upward modulation of ventilatory response by hypoxic drive.

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.

Beginning at 2 L/minute and increasing up to 4 to 5 L/minute if CSA continues is recommended.

At higher flow rates, nasal dryness may be problematic, and use of nasal cups, humidification, or a full face mask may alleviate this problem.

associated with end-stage renal disease (ESRD) on dialysis

Consider – consider changes to dialysis regimen

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Consider –

consider changes to dialysis regimen

Treatment recommended for SOME patients in selected patient group

Despite limited observational data available in end-stage renal disease-related CSA, bicarbonate buffer dialysis is preferred over acetate buffer dialysis by showing fewer CSA events. Decreased CSA events were also observed in nocturnal dialysis in comparison to conventional daytime hemodialysis.

without Cheyne-Stokes breathing: primary (idiopathic)

1st line – continuous positive airway pressure

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1st line –

continuous positive airway pressure

Because the long-term consequences or complications of primary CSA are not known, symptomatic improvement is probably most important.

Primary CSA is unusual, and there is a paucity of published trials to provide strong evidence for a preferred treatment modality.

Continuous positive airway pressure delivers a constant preset pressure to the airways, and leads to normalization of the apnea-hypopnea index (AHI) in some patients.

Ideally initiated after expert mask fitting and patient education including familiarization with the procedures and equipment. 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.

2nd line – adaptive servoventilation

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2nd line –

adaptive servoventilation

Because the long-term consequences or complications of idiopathic CSA are not known, symptomatic improvement is probably most important. Primary CSA is unusual, and there is a paucity of published trials to provide strong evidence for a preferred treatment modality.

Adaptive servoventilation (ASV) evaluates the patient's ventilatory patterns, and delivers variable pressure support and ventilatory rate support according to proprietary algorithms in order to reduce hypoventilation and hyperventilatory overshoot.

ASV has been more consistent in controlling sleep-disordered breathing in these patients compared with continuous positive airway pressure (CPAP).[49]

Ideally initiated after expert mask fitting and patient education including familiarization with the procedures and equipment.

Best begun during attended polysomnography, with end-expiratory pressure set at 4 cm H₂O. Depending upon the device used, most often the rate and inspiratory pressure are automatically adjusted. End-expiratory pressure is then titrated up, to eliminate obstructive events, normalize breathing, and improve sleep architecture.

Note that although ASV appears to more reliably control CSA in patients without Cheyne-Stokes breathing (idiopathic or due to medical conditions), some guidelines require proof that CPAP is ineffective before trials of ASV are recommended.

ASV is contraindicated in patients with symptomatic heart failure with ejection fraction ≤45% even though it effectively reduces the apnea-hypopnea index, due to data that show no improvement in cardiovascular outcomes and increased mortality in this patient population.[22][39][46]

3rd line – supplemental oxygen

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3rd line –

supplemental oxygen

Primary CSA is unusual, so there is a paucity of published trials to provide strong evidence for a preferred treatment modality.

If adaptive servoventilation and continuous positive airway pressure prove ineffective, supplemental oxygen provided through a nasal cannula at 2 to 4 L/minute has been shown to decrease central apnea-hypopnea index in a small series, but is also not uniformly successful.

Supplemental oxygen attempts to significantly reduce upward modulation of ventilatory response by hypoxic drive.

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.

Beginning at 2 L/minute and increasing up to 4 to 5 L/minute if CSA continues is recommended.

At higher flow rates, nasal dryness may be problematic, and use of nasal cups, humidification, or a full face mask may alleviate this problem.

4th line – acetazolamide or zolpidem or triazolam

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4th line –

acetazolamide or zolpidem or triazolam

Idiopathic CSA is unusual, so there is a paucity of published trials to provide strong evidence for a preferred treatment modality.

There are limited data that show improvement in the apnea-hypopnea index (AHI) with acetazolamide in idiopathic CSA. Acetazolamide can be considered in the treatment of idiopathic CSA, but side effects frequently occur.[45][50][51]

Zolpidem and triazolam also have limited data showing a reduction in AHI and can be considered treatment options in primary CSA if there are no risk factors for underlying respiratory depression, and with close clinical follow-up, if other therapies fail.[45][52][53]

Zolpidem (immediate release) is used off-label in patients with CSA and caution should be exercised in these patients as zolpidem may cause next-morning drowsiness, particularly in women. Therefore, lower doses may be considered and effectiveness followed carefully.[52][75]

Primary options

acetazolamide: 250 mg orally once to twice daily

zolpidem: consult specialist for guidance on dose

triazolam: 0.125 to 0.25 mg once daily at bedtime

with Cheyne-Stokes breathing

1st line – optimize underlying medical condition

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1st line –

optimize underlying medical condition

Abnormal breathing and sleep patterns may resolve once management of the underlying condition (e.g., congestive heart failure [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.

2nd line – continuous positive airway pressure

Back

2nd line –

continuous positive airway pressure

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.

Ideally initiated after expert mask fitting and patient education including familiarization with the procedures and equipment.

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 apnea-hypopnea index (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.

Implementation of continuous positive airway pressure (CPAP) is recommended for patients with heart failure 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-Cheyne-Stokes breathing 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 (LVEF) and blood pressure and a moderate decrease in BNP.[22]

A meta-analysis evaluating positive pressure therapy (adaptive servoventilation 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.

3rd line – supplemental nocturnal oxygen therapy

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3rd line –

supplemental nocturnal oxygen therapy

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.

Beginning at 2 L/minute and increasing up to 4 to 5 L/minute if CSA continues is recommended.[76][77]

Oxygen is typically supplied through a nasal cannula. It is usually attempted if continuous positive airway pressure is not available or is contraindicated. Nocturnal oxygen improves oxygen saturation and ejection fraction and reduces the number of respiratory events without clinically significant adverse effects. Whether or not targeting nocturnal hypoxemia is associated with beneficial effects on mortality remains to be determined.

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.

4th line – positive pressure ventilation: bilevel positive airway pressure with spontaneous/timed back up rate

Back

4th line –

positive pressure ventilation: bilevel positive airway pressure with spontaneous/timed back up rate

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: end-expiratory pressure 5 cm H₂O, inspiratory pressure 9 to 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.

5th line – cardiac resynchronization therapy or acetazolamide or theophylline

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5th line –

cardiac resynchronization therapy or acetazolamide or theophylline

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]

Primary options

acetazolamide: 250 mg orally once to four times daily

theophylline: 3.3 mg/kg orally (extended-release) twice daily, monitor theophylline blood level and adjust dose to avoid toxicity

due to high-altitude periodic breathing

1st line – return to lower altitude or sea level

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1st line –

return to lower altitude or sea level

Returning to sea level or quickly descending to a lower altitude will result in improvement or disappearance of high-altitude periodic breathing. This occurs because of the increase in the partial pressure of oxygen, which eliminates the hypoxia-driven hyperventilation.

2nd line – supplemental oxygen

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2nd line –

supplemental oxygen

Supplemental oxygen during sleep decreases periodic breathing and apnea-hypopnea index, improves subjective sleep quality, and reduces acute mountain sickness score.[78][79]

Supplemental oxygen may be a useful temporizing measure while awaiting return to lower altitude.

3rd line – acetazolamide

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3rd line –

acetazolamide

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 continuous positive airway pressure (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.

Primary options

acetazolamide: 250 mg orally once to four times daily

due to medication or substance misuse

1st line – remove or reduce dose of culprit drug

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1st line –

remove or reduce dose of culprit drug

Candidates most often include an opioid medication that was initiated or increased in dosage just prior to onset of symptoms. Ataxic breathing is more frequent at a morphine equivalent daily dose of 200 mg/day or higher.[34]

2nd line – adaptive servoventilation

Back

2nd line –

adaptive servoventilation

Evaluates the patient's ventilatory patterns, and delivers variable pressure support and ventilatory rate support according to proprietary algorithms in order to reduce hypoventilation and hyperventilatory overshoot.

There are mixed data about the efficacy of adaptive servoventilation (ASV) compared with continuous positive airway pressure (CPAP) in treatment of opioid-induced CSA.[68][69] Because some patients may respond to CPAP alone, it is not unreasonable to first try CPAP, although for most patients ASV will provide more reliable improvements in breathing parameters.

Expert mask fitting and patient education including familiarization with the procedures and equipment should precede initiation. Expiratory pressure is started at 4 cm H₂O, then adjusted during polysomnography to eliminate obstructive breathing events, ideally while the patient is in nonrapid eye movement supine sleep, when CSA events would be expected to be most severe.

The inspiratory pressure is typically determined by the machine, and back-up rates may be either set or left to a default algorithm whereby the machine attempts to normalize respiratory patterns.

ASV is contraindicated in patients with symptomatic heart failure with ejection fraction ≤45% even though it effectively reduces the AHI, due to data that show no improvement in cardiovascular outcomes and increased mortality in this patient population.[22][39][46]

If opioid-induced alveolar hypoventilation is suspected, a trial of noninvasive positive pressure ventilation (bilevel positive airway pressure with spontaneous/timed back up rate) to secure a minute ventilation should be considered instead of ASV.

2nd line – positive pressure ventilation: bilevel positive airway pressure with back up rate

Back

2nd line –

positive pressure ventilation: bilevel positive airway pressure with back up rate

If opioid-induced alveolar hypoventilation is suspected, a trial of noninvasive positive pressure ventilation should be considered before adaptive servoventilation.[71]

Usually delivered by a bilevel positive airway pressure device, whereby one sets the inspiratory and expiratory pressure supports, as well as the spontaneously-timed back-up ventilatory rate (BPAP-ST).

If adaptive servoventilation is not indicated due to alveolar hypoventilation, BPAP-ST has been shown to improve apnea-hypopnea index (AHI), but no long-term data are available.

Initiation follows expert mask fitting and patient education including familiarization with the procedures and equipment.

Typical initial settings: end-expiratory pressure 5 cm H₂O, inspiratory pressure 10 to 12 cm H₂O, and back-up rate 12 to 14.

Pressures are then adjusted in an attempt to normalize the AHI and to eliminate sustained oxygen desaturation.

3rd line – continuous positive airway pressure

Back

3rd line –

continuous positive airway pressure

Continuous positive airway pressure delivers a constant preset pressure to the airways, and responsiveness in patients for whom adjustment of culprit medications is impractical or has been ineffective is similar to responsiveness in other types of CSA.

Ideally initiated after expert mask fitting and patient education including familiarization with the procedures and equipment.

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 apnea-hypopnea index and sleep architecture.

treatment-emergent CSA

1st line – continuous positive airway pressure

Back

1st line –

continuous positive airway pressure

Although this mode of therapy may be effective in some patients, as they tend to improve with long-term continuous positive airway pressure (CPAP), there is a substantial group with persistently elevated CSA events. Unfortunately, there are not well defined clinical or polysomnographic criteria to preemptively identify the 30% subgroup of CPAP nonresponders. A close clinical follow-up for 2 to 3 months, regarding treatment compliance, symptomatology improvement, and resolution of central events as per CPAP download information, could support continuation with CPAP treatment.

2nd line – adaptive servoventilation

Back

2nd line –

adaptive servoventilation

The adaptive servoventilation (ASV) has emerged as a highly effective treatment option for patients with treatment-emergent CSA. Several studies of ASV have demonstrated marked improvement in apnea-hypopnea index (AHI), sleep consolidation, and improvement of daytime sleepiness in comparison to continuous positive airway pressure and bilevel positive airway pressure with back up rate treatment.[66][73]

The inspiratory pressure is typically determined by the machine, and back-up rates may be either set or left to a default algorithm whereby the machine attempts to normalize respiratory patterns.

3rd line – positive pressure ventilation: bilevel positive airway pressure with back up rate

Back

3rd line –

positive pressure ventilation: bilevel positive airway pressure with back up rate

Usually delivered by a bilevel positive airway pressure device, whereby one sets the inspiratory and expiratory pressure supports, as well as the back-up ventilatory rate (BPAP-ST).

If adaptive servoventilation is not available, or is not effective, BPAP-ST has been shown to improve apnea-hypopnea index (AHI), but no long-term data are available. However, total arousal index and respiratory arousal index were not significantly different than for the continuous positive airway pressure treatment group, showing a persistence of fragmented sleep.[66] Initiation follows expert mask fitting and patient education including familiarization with the procedures and equipment.

Typical initial settings: end-expiratory pressure 5 cm H₂O, inspiratory pressure 9 to 10 cm H₂O, and back-up rate 12 to 14. Pressures are then adjusted in an attempt to normalize 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.

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Central sleep apnea

Treatment algorithm

without Cheyne-Stokes breathing: due to medical disorder

positive airway pressure: continuous positive airway pressure or adaptive servoventilation

supplemental oxygen

consider changes to dialysis regimen

without Cheyne-Stokes breathing: primary (idiopathic)

continuous positive airway pressure

adaptive servoventilation

supplemental oxygen

acetazolamide or zolpidem or triazolam

Primary options

with Cheyne-Stokes breathing

optimize underlying medical condition

continuous positive airway pressure

supplemental nocturnal oxygen therapy

positive pressure ventilation: bilevel positive airway pressure with spontaneous/timed back up rate

cardiac resynchronization therapy or acetazolamide or theophylline

Primary options

due to high-altitude periodic breathing

return to lower altitude or sea level

supplemental oxygen

acetazolamide

Primary options

due to medication or substance misuse

remove or reduce dose of culprit drug

adaptive servoventilation

positive pressure ventilation: bilevel positive airway pressure with back up rate

continuous positive airway pressure

treatment-emergent CSA

continuous positive airway pressure

adaptive servoventilation

positive pressure ventilation: bilevel positive airway pressure with back up rate